U.S. patent application number 16/387178 was filed with the patent office on 2019-12-19 for insulin glargine/lixisenatide fixed ratio formulation.
The applicant listed for this patent is Sanofi-Aventis Deutschland GmbH. Invention is credited to Louise Silvestre, Elisabeth Souhami.
Application Number | 20190381145 16/387178 |
Document ID | / |
Family ID | 54848560 |
Filed Date | 2019-12-19 |
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United States Patent
Application |
20190381145 |
Kind Code |
A1 |
Souhami; Elisabeth ; et
al. |
December 19, 2019 |
INSULIN GLARGINE/LIXISENATIDE FIXED RATIO FORMULATION
Abstract
The present invention refers to a pharmaceutical composition
comprising (a) lixisenatide or/and a pharmaceutically acceptable
salt thereof, and (b) insulin glargine or/and a pharmaceutically
acceptable salt thereof, wherein the compound (b) and compound (a)
are present in a fixed ratio.
Inventors: |
Souhami; Elisabeth; (Paris,
FR) ; Silvestre; Louise; (Paris, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sanofi-Aventis Deutschland GmbH |
Frankfurt |
|
DE |
|
|
Family ID: |
54848560 |
Appl. No.: |
16/387178 |
Filed: |
April 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15914197 |
Aug 10, 2018 |
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16387178 |
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14965586 |
Dec 10, 2015 |
9950039 |
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15914197 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 38/26 20130101; A61K 38/26 20130101; A61P 5/00 20180101; A61K
2300/00 20130101; A61P 5/50 20180101; A61K 38/28 20130101; A61P
3/10 20180101; A61K 2300/00 20130101; A61K 38/28 20130101 |
International
Class: |
A61K 38/26 20060101
A61K038/26; A61K 38/28 20060101 A61K038/28 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 2014 |
EP |
14197685.2 |
Nov 10, 2015 |
EP |
15193940.2 |
Claims
1: A method of improving glycemic control in a patient with type 2
diabetes mellitus uncontrolled on basal insulin, the method
comprising administering to the patient in need thereof a
pharmaceutical composition comprising: (a) lixisenatide or a
pharmaceutically acceptable salt thereof at a concentration of 33
.mu.g/mL, and (b) insulin glargine or a pharmaceutically acceptable
salt thereof at a concentration of 100 units/mL; wherein the
patient has been treated with a stable dose of between 15 units and
40 units basal insulin per day; and wherein the patient has a HbA1c
level between 7.5% and 10% and a fasting plasma glucose (FPG)
concentration less than or equal to 180 mg/dL (10.0 mmol/L).
2: The method of claim 1, wherein the patient has a HbA1c level
between 7.5% and 10% and a fasting plasma glucose (FPG)
concentration less than or equal to 140 mg/dL (7.8 mmol/L).
3: The method of claim 1, wherein the patient has a body mass index
(BMI) between 20 kg/m.sup.2 to 40 kg/m.sup.2.
4: The method of claim 1, wherein the patient has been treated with
basal insulin for at least 6 months.
5: The method of claim 4, wherein the patient has been treated with
the stable dose of basal insulin for at least 2 months.
6: The method of claim 1, wherein the patient has been treated
basal insulin and 1 or 2 oral anti-diabetic drugs (OADs), wherein
the OADs comprise metformin, a sulfonylurea, a glinide, a sodium
glucose co-transporter 2 (SGLT-2) inhibitor, or a
dipeptidyl-peptidase 4 (DPP-4) inhibitor.
7: The method of claim 6, wherein the patient has been treated with
the stable dose of basal insulin and 1 or 2 OADs for at least 3
months.
8: The method of claim 6, wherein the patient has been treated with
metformin at a dose of at least 1.0 grams per day.
9: A method of improving glycemic control in a patient with type 2
diabetes mellitus uncontrolled on treatment with metformin alone,
the method comprising administering to the patient in need thereof
a pharmaceutical composition comprising: (a) lixisenatide or a
pharmaceutically acceptable salt thereof at a concentration of 33
.mu.g/mL, and (b) insulin glargine or a pharmaceutically acceptable
salt thereof at a concentration of 100 U/mL; wherein the patient
has been treated with metformin alone at a dose of at least 1.0
grams per day for at least 3 months; and wherein the patient has a
HbA1c level between 7.5% and 10%.
10: The method of claim 9, wherein the patient has a body mass
index (BMI) between 20 kg/m.sup.2 to 40 kg/m.sup.2.
11: A method of improving glycemic control in a patient with type 2
diabetes mellitus uncontrolled on treatment with metformin and a
second oral anti-diabetic drug (OAD), the method comprising
administering to the patient in need thereof a pharmaceutical
composition comprising: (a) lixisenatide or a pharmaceutically
acceptable salt thereof at a concentration of 33 .mu.g/mL, and (b)
insulin glargine or a pharmaceutically acceptable salt thereof at a
concentration of 100 U/mL; wherein the patient has been treated
with metformin and the second OAD for at least 3 months; wherein
the second OAD is a sulfonylurea, a glinide, a sodium glucose
co-transporter 2 (SGLT-2) inhibitor, or a dipeptidyl-peptidase 4
(DPP-4) inhibitor; and wherein the patient has a HbA1c level
between 7% and 9%.
12: The method of claim 11, wherein the patient has a body mass
index (BMI) between 20 kg/m.sup.2 to 40 kg/m.sup.2.
Description
RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 15/914,197, filed Aug. 10, 2018, which is a division of
U.S. patent application Ser. No. 14/965,586, filed Dec. 10, 2015,
now U.S. Pat. No. 9,950,039, which claims priority to European
Patent Application Nos. 15193940.2, filed Nov. 10, 2015, and
14197685.2, filed Dec. 12, 2014, the entire disclosures of which
are hereby incorporated herein by reference in their entirety.
DESCRIPTION
[0002] Subject of the present invention is a pharmaceutical
composition comprising (a) lixisenatide or/and a pharmaceutically
acceptable salt thereof, and (b) insulin glargine or/and a
pharmaceutically acceptable salt thereof, wherein the compound (b)
and compound (a) are present in a ratio of about 2.6 to about 3.4 U
of compound (b) per .mu.g of compound (a).
[0003] In a healthy person the release of insulin by the pancreas
is strictly coupled to the concentration of blood glucose. An
increased level of blood glucose, as appears after meals, is
rapidly counterbalanced by a respective increase in insulin
secretion. In fasting condition the plasma insulin level drops to a
basal value which is sufficient to ensure the continuous supply of
glucose to insulin-sensitive organs and tissues and to keep the
hepatic glucose production at a low level at night.
[0004] In contrast to diabetes type 1, there is not generally a
lack of insulin in diabetes type 2 but in many cases, particularly
in progressive cases, the treatment with insulin is regarded as the
most suitable therapy, if required in combination with orally
administered anti-diabetic drugs.
[0005] An increased glucose level in the blood over several years
without initial symptoms represents a significant health risk. It
could clearly be shown by the large-scale DCCT study in the USA
(The Diabetes Control and Complications Trial Research Group (1993)
N. Engl. J. Med. 329, 977-986) that chronically increased levels of
blood glucose are a main reason for the development of diabetes
complications. Examples for diabetes complications are micro and
macrovascular damages that possibly manifest themselves in
retinopathies, nephropathies or neuropathies and lead to blindness,
renal failure and the loss of extremities and are accompanied by an
increased risk of cardiovascular diseases. It can thus be concluded
that an improved therapy of diabetes primarily has to aim keeping
blood glucose in the physiological range as closely as
possible.
[0006] A particular risk exists for overweight patients suffering
from diabetes type 2, e.g. patients with a body mass index
(BMI).gtoreq.30 kg/m.sup.2. In these patients the risks of diabetes
overlap with the risks of overweight, leading e.g. to an increase
of cardiovascular diseases compared with diabetes type 2 patients
being of a normal weight. Thus, it is particularly necessary to
treat diabetes in these patients while reducing the overweight.
[0007] Metformin is a biguanide hypoglycemic agent used in the
treatment of non-insulin-dependent diabetes mellitus (diabetes
mellitus type 2) not responding to dietary modification. Metformin
improves glycemic control by improving insulin sensitivity and
decreasing intestinal absorption of glucose. Metformin is usually
administered orally. However, control diabetes mellitus type 2 in
obese patients by metformin may be insufficient. Thus, in these
patients, additional measures for controlling diabetes mellitus
type 2 may be required.
[0008] The compound desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2
(AVE0010, lixisenatide) is a derivative of Exendin-4. Lixisenatide
is disclosed as SEQ ID NO:93 in WO 01/04156:
TABLE-US-00001 SEQ ID NO: 1: Lixisenatide (44 amino acids)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-
L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K-K-NH.sub.2 SEQ ID NO: 2:
Exendin-4 (39 amino acids)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-
L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH.sub.2
[0009] Exendins are a group of peptides which can lower blood
glucose concentration. The Exendin analogue lixisenatide is
characterised by C-terminal truncation of the native Exendin-4
sequence. Lixisenatide comprises six C-terminal lysine residues not
present in Exendin-4.
[0010] In the context of the present invention, lixisenatide
includes pharmaceutically acceptable salts thereof. The person
skilled in the art knows pharmaceutically acceptable salts of
lixisenatide. A preferred pharmaceutically acceptable salt of
lixisenatide employed in the present invention is acetate.
[0011] Insulin glargine is 31.sup.B-32.sup.B-Di-Arg human insulin,
an analogue of human insulin, with further substitution of
asparagine in position A21 by glycine. Insulin glargine is also
termed Gly(A21)-Arg(B31)-Arg(B32)-human insulin. In the present
invention, insulin glargine includes pharmaceutically acceptable
salts thereof.
[0012] Insulin glargine is disclosed in U.S. Pat. No.
5,656,722.
[0013] Lantus.RTM. is an insulin product containing insulin
glargine providing 24 hours basal insulin supply after single dose
subcutaneous injection.
[0014] A dose of 100 U insulin glargine requires injection of 1 mL
Lantus.RTM. U100, each mL Lantus.RTM. U100 contains 100 U insulin
glargine. 100 U insulin glargine correspond to 3.6378 mg insulin
glargine.
[0015] WO 2011/147980 discloses an on-site mixture comprising a
fixed concentration of insulin glargine and a variable
concentration of lixisenatide. This document also discloses an
exemplary on-site mixed preparation containing 100 U/mL insulin
glargine and 66.67 .mu.g/mL (or 800/300*25 .mu.g/mL) lixisenatide,
60.6 .mu.g/mL (or 800/330*25 .mu.g/mL) lixisenatide, 55.56 .mu.g/mL
(or 800/360*25 .mu.g/mL) lixisenatide, 51.28 .mu.g/mL lixisenatide
(or 800/390*25 .mu.g/mL lixisenatide), 47.62 .mu.g/mL (or
800/420*25 .mu.g/mL) lixisenatide, 44.44 .mu.g/mL (or 800/450*25
.mu.g/mL) lixisenatide, 41.67 .mu.g/mL (or 800/480*25 .mu.g/mL)
lixisenatide, 39.22 .mu.g/mL (or 800/510*25 .mu.g/mL) lixisenatide,
37.04 .mu.g/mL (or 800/540*25 .mu.g/mL) lixisenatide, 35.09
.mu.g/mL (or 800/570*25 .mu.g/mL) lixisenatide, or 33.33 .mu.g/mL
(or 800/600*25 .mu.g/mL) lixisenatide.
[0016] Example 1 describes a randomized, 30-week,
active-controlled, open label, 2 treatment-arm, parallel-group,
multicenter study comparing the efficacy and safety of the insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
with or without metformin in patients with T2DM. In this study, (I)
a pharmaceutical composition comprising 100 U/ml insulin glargine
and 50 .mu.g/mL lixisenatide, and (II) a pharmaceutical composition
comprising 100 U/ml insulin glargine and 33 .mu.g/mL lixisenatide
is used. Furthermore, a combination of (I) and (II) is used.
[0017] Example 2 describes a randomized, 3-treatment arm clinical
study comparing the efficacy and safety of insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
alone and to lixisenatide alone on top of metformin in patients
with type 2 diabetes mellitus.
[0018] Example 2 demonstrates statistical superiority of the fixed
ratio combination compared to insulin glargine on HbA1c change as
well as statistical superiority of the fixed ratio combination over
lixisenatide (Table 9 of Example 2).
[0019] Example 2 demonstrates that significantly more patients
treated with the fixed ratio combination reached an HbA1c<7% and
HbA1c.ltoreq.6.5% compared to those receiving insulin glargine or
lixisenatide (Table 10 of Example 2).
[0020] Example 2 demonstrates that treatment with the fixed ratio
formulation significantly improved postprandial glycemic control.
The 2-hour glucose excursion was significantly improved compared
with treatment with insulin glargine (Table 11 of Example 2). An
improvement by the fixed dose ratio formulation was also observed
for the 2-hour postprandial plasma glucose (PPG) compared with
lixisenatide and insulin glargine (Table 12).
[0021] Body weight decreased in the fixed ratio combination and
lixisenatide groups and increased in the insulin glargine group. A
statistically significant difference in the body weight change was
found between the fixed ratio combination group and the insulin
glargine group (Table 13).
[0022] The reductions in fasting plasma glucose (FPG) were similar
in the fixed ratio combination and the insulin glargine group, and
it was significantly lower in the lixisenatide group (Table
14).
[0023] Patients treated with fixed ratio combination had a
statistically significant greater decrease in average 7-point SMPG
profile compared to patients treated with insulin glargine and
patients treated with lixisenatide respectively (Table 15).
[0024] In the clinical trial described in Example 2, a higher
proportion of patients reached the composite endpoint of
HbA1c<7.0% with no body weight gain in the fixed ratio
combination group compared to the insulin glargine group and the
lixisenatide group (Table 16). More patients reached the triple
composite endpoint of HbA1c<7.0% with no body weight gain and
with no documented (plasma glucose concentration.ltoreq.70 mg/dL
[3.9 mmol/L]) symptomatic hypoglycemia during the study in the
fixed dose ration composition group compared to the insulin
glargine group and the lixisenatide group, respectively (Table
17).
[0025] In summary, the fixed ratio combination added to metformin
for patients not well controlled with metformin with or without a
second oral antidiabetic drug (OAD) significantly improved HbA1c
and reduced 2-hour glucose excursions and 2-hour PPG, average
7-point SMPG and body weight in comparison to insulin glargine. The
combination also significantly improved HbA1c, FPG, and average
7-point SMPG in comparison with lixisenatide.
[0026] The advantages of starting with the fixed ratio combination
compared to starting with each component alone in patients not well
controlled on an oral antidiabetic drug is therefore evidenced
based on the advantages demonstrated for HbA1c and body weight vs
insulin glargine, and for HbA1c, FPG and gastrointestinal
tolerability in comparison to lixisenatide.
[0027] Example 3 describes a randomized, 2-treatment arm clinical
study comparing the efficacy and safety of insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
with or without metformin in patients with type 2 diabetes
mellitus.
[0028] The fixed ratio combination with or without metformin for
patients not adequately controlled with basal insulin with or
without oral antidiabetic drugs significantly improved HbA1c (Table
8 of Example 3), allowed more patients to reach HbA1c treatment
target (Table 9), reduced 2-hour glucose excursions (Table 10) and
2-hour PPG (Table 11), average 7-point SMPG (Table 13) and body
weight (Table 12) in comparison to insulin glargine.
[0029] A first aspect of the present invention is a pharmaceutical
composition comprising [0030] Lixisenatide
(desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2) or/and a
pharmaceutically acceptable salt thereof, and [0031] insulin
glargine or/and a pharmaceutically acceptable salt thereof, wherein
the compound (b) and compound (a) are present in a ratio of about
2.6 to about 3.4 U of compound (b) per .mu.g of compound (a).
[0032] Compound (b) and compound (a) can also be present in a ratio
of about 2.8 to about 3.2 U of compound (b) per .mu.g of compound
(a). Compound (b) and compound (a) can also be present in a ratio
of about 2.9 to about 3.1 U of compound (b) per .mu.g of compound
(a). Compound (b) and compound (a) can also be present in a ratio
of about 3 U of compound (b) per .mu.g of compound (a).
[0033] The concentration ratio of compound (b) to compound (a) in
the pharmaceutical composition as described herein is a fixed
ratio.
[0034] In the present invention, compound (a) and compound (b) are
provided in a single composition in a pre-determined fixed ratio.
Also within the scope of the present invention are two separate
compositions, the first composition comprising compound (a) and the
second composition comprising compound (b), to be administered to a
patient in need thereof as defined herein, in a fixed ratio as
defined herein.
[0035] In the composition of the present invention, the
concentration of compound (a) is preferably not a concentration
selected from 66.67 .mu.g/mL 60.6 .mu.g/mL, 55.56 .mu.g/mL, 51.28
.mu.g/mL, 47.62 .mu.g/mL, 44.44 .mu.g/mL, 41.67 .mu.g/mL, 39.22
.mu.g/mL, 37.04 .mu.g/mL, and 35.09 .mu.g/mL.
[0036] In the composition of the present invention, the
concentration of compound (a) is preferably not a concentration
selected from 800/300*25 .mu.g/mL, 800/330*25 .mu.g/mL, 800/360*25
.mu.g/mL, 800/390*25 .mu.g/mL, 800/420*25 .mu.g/mL, 800/450*25
.mu.g/mL, 800/480*25 .mu.g/mL, 800/510*25 .mu.g/mL, 800/540*25
.mu.g/mL and 800/570*25 .mu.g/mL.
[0037] In the composition of the present invention, the
concentration of compound (a) can be in the range of 25-40
.mu.g/ml. The concentration ratio of compound (b) to compound (a)
can be in the range of 2.6 to 3.4 U/.mu.g, 2.8 to 3.2 U/.mu.g, 2.9
to 3.1 U/.mu.g or about 3 U/.mu.g.
[0038] In the composition of the present invention, the
concentration of compound (b) can be in the range of 65-136 U/ml,
70-128 U/ml, 72.5-124 U/ml or 75-120 U/ml.
[0039] In the composition of the present invention, the
concentration of compound (a) can be in the range of 25-40
.mu.g/ml, and the concentration of compound (b) can be in the range
of 65-136 U/mL, 70-128 U/mL, 72.5-124 U/mL or 75-120 U/mL.
[0040] In the composition of the present invention, the
concentration of compound (a) can be in the range of 25-38
.mu.g/ml. The concentration ratio of compound (b) to compound (a)
can be in the range of 2.6 to 3.4 U/.mu.g, 2.8 to 3.2 U/.mu.g, 2.9
to 3.1 U/.mu.g or about 3 U/.mu.g.
[0041] In the composition of the present invention, the
concentration of compound (b) can be in the range of 65-129.2 U/ml,
70-121.6 U/ml, 72.5-117.8 U/ml or 75-114 U/ml.
[0042] In the composition of the present invention, the
concentration of compound (a) can be in the range of 25-38
.mu.g/ml, and the concentration of compound (b) can be in the range
of 65-129.2 U/ml, 70-121.6 U/ml, 72.5-117.8 U/ml or 75-114
U/ml.
[0043] In the composition of the present invention, the
concentration of compound (a) can be in the range of 30-35
.mu.g/ml. The concentration ratio of compound (b) to compound (a)
can be in the range of 2.6 to 3.4 U/.mu.g, 2.8 to 3.2 U/.mu.g, 2.9
to 3.1 U/.mu.g or about 3 U/.mu.g.
[0044] In the composition of the present invention, the
concentration of compound (b) can be in the range of 78-119 U/mL,
84-112 U/mL, 87-108.5 U/mL, or 90-105 U/mL.
[0045] In the composition of the present invention, the
concentration of compound (a) can be in the range of 30-35
.mu.g/mL, and the concentration of compound (b) can be in the range
of 78-119 U/mL, 84-112 U/mL, 87-108.5 U/mL, or 90-105 U/mL.
[0046] In the pharmaceutical composition, the concentration of
compound (a) can also be about 33 .mu.g/mL or about 33.3 .mu.g/mL.
The concentration ratio of compound (b) to compound (a) can be in
the range of 2.6 to 3.4 U/.mu.g, 2.8 to 3.2 U/.mu.g, 2.9 to 3.1
U/.mu.g, or about 3 U/.mu.g. The concentration of compound (b) can
be in the range of 85.8-112.2 U/mL, 92.4-105.6 U/mL, 95.7-102.3
U/mL, or can be about 100 U/mL.
[0047] In particular, the concentration ratio of compound (b) to
compound (a) is about 3 U/.mu.g. More particularly, in the
composition having a concentration ratio of compound (b) to
compound (a) of about 3 U/.mu.g, the concentration of compound (a)
is about 33 .mu.g/mL or about 33.3 .mu.g/mL, and the concentration
of compound (b) is about 100 U/mL.
[0048] If the pharmaceutical composition as described herein
comprises compound (a) in a concentration range of 25 to 40
.mu.g/mL, the concentration of compound (a) is preferably not a
concentration selected from 39.22 .mu.g/mL, 37.04 .mu.g/mL and
35.09 .mu.g/mL. In the concentration range of 25 to 40 .mu.g/mL,
the concentration of compound (a) preferably is not a concentration
selected from 800/510*25 .mu.g/mL, 800/540*25 .mu.g/mL, 800/570*25
.mu.g/mL.
[0049] If the pharmaceutical composition as described herein
comprises compound (a) in a concentration range of 25 to 38
.mu.g/mL, the concentration of compound (a) is preferably not a
concentration selected from 37.04 .mu.g/mL and 35.09 .mu.g/mL. In
the concentration range of 25 to 38 .mu.g/mL, the concentration of
compound (a) preferably is not a concentration selected from
800/540*25 .mu.g/mL, 800/570*25 .mu.g/mL.
[0050] Yet another aspect of the present invention is a combination
comprising
[0051] (I) a pharmaceutical composition comprising [0052]
Lixisenatide (desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2)
or/and a pharmaceutically acceptable salt thereof, and [0053]
insulin glargine or/and a pharmaceutically acceptable salt thereof,
wherein the compound (b) and compound (a) are present in a ratio of
about 1.6 to about 2.4 U of compound (b) per .mu.g of compound (a),
and
[0054] (II) a pharmaceutical composition comprising [0055]
Lixisenatide (desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2)
or/and a pharmaceutically acceptable salt thereof, and [0056]
insulin glargine or/and a pharmaceutically acceptable salt thereof,
wherein the compound (b) and compound (a) are present in a ratio of
about 2.6 to about 3.4 U of compound (b) per .mu.g of compound
(a).
[0057] In the combination, composition (II) can be a composition
covered by the ratio of about 2.6 to about 3.4 U of compound (b)
per .mu.g of compound (a) as described herein.
[0058] The combination of the present invention can be used in the
treatment of any disease or condition described herein.
[0059] In composition (I), compound (b) and compound (a) can also
be present in a ratio of about 1.8 to about 2.2 U of compound (b)
per .mu.g of compound (a). Compound (b) and compound (a) can also
be present in a ratio of about 1.9 to about 2.1 U of compound (b)
per .mu.g of compound (a). Compound (b) and compound (a) can also
be present in a ratio of about 2 U of compound (b) per .mu.g of
compound (a).
[0060] In composition (I), the concentration ratio of compound (b)
to compound (a) is a fixed ratio.
[0061] In composition (I), the concentration of compound (a) can be
in the range of 40-60 .mu.g/ml. The concentration ratio of compound
(b) to compound (a) can be in the range of 1.6 to 2.4 U/.mu.g, 1.8
to 2.2 U/.mu.g, 1.9 to 2.1 U/.mu.g or about 2 U/.mu.g.
[0062] In composition (I), the concentration of compound (b) can be
in the range of 64-144 U/ml, 72-132 U/ml, 76-126 U/ml or 80-120
U/ml.
[0063] In composition (I), the concentration of compound (a) can be
in the range of 40-60 .mu.g/ml, and the concentration of compound
(b) can be in the range of 64-144 U/ml, 72-132 U/ml, 76-126 U/ml or
80-120 U/ml.
[0064] In composition (I), the concentration of compound (a) can be
in the range of 45-55 .mu.g/ml. The concentration ratio of compound
(b) to compound (a) can be in the range of 1.6 to 2.4 U/.mu.g, 1.8
to 2.2 U/.mu.g, 1.9 to 2.1 U/.mu.g or about 2 U/.mu.g.
[0065] In composition (I), the concentration of compound (b) can be
in the range of 72-132 U/ml, 81-121 U/ml, 85.5-115.5 U/ml, or
90-110 U/ml.
[0066] In composition (I), the concentration of compound (a) can be
in the range of 45-55 .mu.g/ml, and the concentration of compound
(b) can be in the range of 72-132 U/ml, 81-121 U/ml, 85.5-115.5
U/ml, or 90-110 U/ml.
[0067] In composition (I), the concentration of compound (a) can
also be about 50 .mu.g/mL. The concentration ratio of compound (b)
to compound (a) can be in the range of 1.6 to 2.4 U/.mu.g, 1.8 to
2.2 U/.mu.g, 1.9 to 2.1 U/.mu.g or about 2 U/.mu.g. The
concentration of compound (b) can be in the range of 80-120 U/ml,
90-110 U/ml, 95-105 U/ml, or can be about 100 U/ml.
[0068] In particular, in composition (I), the concentration of
compound (a) is about 50 .mu.g/ml, and the concentration of
compound (b) is about 100 U/ml.
[0069] If the pharmaceutical composition (I) comprises compound (a)
in a concentration range of 40 to 60 .mu.g/ml, the concentration of
compound (a) preferably is not a concentration selected from 55.56
.mu.g/mL, 51.28 .mu.g/mL, 47.62 .mu.g/mL, 44.44 .mu.g/mL, and 41.67
.mu.g/mL. In the concentration range of 40 to 60 .mu.g/ml, the
concentration of compound (a) preferably is not a concentration
selected from 800/360*25 .mu.g/mL, 800/390*25 .mu.g/mL, 800/420*25
.mu.g/mL, 800/450*25 .mu.g/mL, and 800/480*25 .mu.g/mL.
[0070] If the pharmaceutical composition (I) comprises compound (a)
in a concentration range of 45 to 55 .mu.g/ml, the concentration of
compound (a) is preferably not a concentration selected from 51.28
.mu.g/mL and 47.62 .mu.g/mL. In the concentration range of 45 to 55
.mu.g/ml, the concentration of compound (a) preferably is not a
concentration selected from 800/390*25 .mu.g/mL and 800/420*25
.mu.g/mL.
[0071] The pharmaceutical composition as described herein
preferably is not an on-site mixed composition or formulation. The
on-site mixed composition or formulation is prepared "on-site", for
example shortly (e.g. less than 10 min, less than 20 min or less
than 30 min) before administration or/and in the presence of the
patient to be treated. In this context, an on-site mixed
composition or formulation can be a composition or formulation
prepared from at least two separate compositions, each comprising
at least one of lixisenatide and insulin glargine. In particular,
an on-site mixed formulation or composition is a composition
prepared from two separate compositions, the first composition
comprising lixisenatide and insulin glargine, and the second
composition comprising insulin glargine. More particular, in this
context, the on-site mixed formulation or composition is prepared
from a first composition containing 800 .mu.g/mL lixisenatide and
100 U/mL insulin glargine, and a second composition containing 100
U/ml insulin glargine. In this context, the on-site mixed
composition or formulation can comprise a fixed volume of the first
composition and a variable volume of the second composition.
[0072] In particular, a pharmaceutical composition (I) comprising 2
U insulin glargine per .mu.g lixisenatide, as described herein or
(II) 3 U insulin glargine per .mu.g lixisenatide is not an on-site
mixed composition.
[0073] The composition or combination of the present invention can
be used for the treatment of diabetes mellitus type 1 or/and 2
patients, or/and for the treatment of conditions associated with
diabetes type diabetes mellitus type 1 or/and 2.
[0074] In particular the composition or combination of the present
invention can be used for the treatment of diabetes mellitus type 2
patients, or/and for the treatment of conditions associated with
diabetes type diabetes mellitus type 2. Such conditions include a
decrease of glucose tolerance, an increased postprandial plasma
glucose concentration, an increase in fasting plasma glucose
concentration, or/and an increased HbA.sub.1c value, compared for
example with persons not suffering from diabetes type 2 or with a
normoglycemic condition.
[0075] The composition or combination of the present invention can
be used in glycemic control in diabetes type 2 patients. In the
present invention, "improvement of glycemic control" or "glycemic
control" in particular refers to improvement of glucose tolerance,
improvement of postprandial plasma glucose concentration,
improvement of fasting plasma glucose concentration, or/and
improvement of the HbA.sub.1c value.
[0076] In particular, improvement of glucose tolerance includes
improvement of the postprandial plasma glucose concentration,
improvement of the postprandial plasma glucose excursion or/and
improvement of fasting plasma glucose concentration. More
particular, improvement of glucose tolerance includes improvement
of the postprandial plasma glucose concentration.
[0077] In particular, improvement of postprandial plasma glucose
concentration is reduction of the postprandial plasma glucose
concentration. Reduction means in particular that the plasma
glucose concentration reaches normoglycemic values or at least
approaches these values.
[0078] In particular, improvement of postprandial plasma glucose
excursion is reduction of the postprandial plasma glucose
excursion. Reduction means in particular that the plasma glucose
excursion reaches normoglycemic values or at least approaches these
values.
[0079] In particular, improvement of fasting plasma glucose
concentration is reduction of the fasting plasma glucose
concentration. Reduction means in particular that the plasma
glucose concentration reaches normoglycemic values or at least
approaches these values.
[0080] In particular, improvement of the HbA.sub.1c value is
reduction of the HbA.sub.1c value. Reduction of the HbA.sub.1c
value in particular means that the HbA.sub.1c value is reduced
below 6.5% or 7%, for example after treatment for at least one
month, at least two months, at least three months, at least four
months, at least five months, at least six months or at least one
year.
[0081] The pharmaceutical composition or combination as described
herein may be administered in combination with metformin or/and a
pharmaceutically acceptable salt thereof, in particular as add-on
to the treatment with metformin or/and a pharmaceutically
acceptable salt thereof. Metformin is the international
nonproprietary name of 1,1-dimethylbiguanide (CAS Number 657-24-9).
In the present invention, the term "metformin" includes any
pharmaceutically acceptable salt thereof.
[0082] In the present invention, metformin may be administered
orally. The skilled person knows formulations of metformin suitable
for treatment of diabetes type 2 by oral administration. Metformin
may be administered to a patient in need thereof, in an amount
sufficient to induce a therapeutic effect. Metformin may be
administered in a dose of at least 1.0 g/day or at least 1.5 g/day.
For oral administration, metformin may be formulated in a solid
dosage form, such as a tablet or pill. Metformin may be formulated
with suitable pharmaceutically acceptable carriers, adjuvants,
or/and auxiliary substances.
[0083] In the present invention, the terms "add-on", "add-on
treatment", "add-on therapy" and "on top of" relate to treatment of
diabetes mellitus type 2 with the metformin and the composition of
the present invention, as described herein. The composition of the
present invention and metformin may be administered by different
administration routes. Metformin may be administered orally, and
the composition of the present invention may be administered
parenterally.
[0084] The patient to be treated by the composition of the present
invention may be a patient suffering from diabetes type 2.
[0085] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may be a patient suffering
from diabetes type 2, wherein diabetes type 2 is not adequately
controlled by treatment with metformin alone, for example by
treatment with metformin for at least 2 or at least 3 months, for
example with a dose of at least 1.0 g/day or at least 1.5 g/day of
metformin. In particular, the diabetes type 2 is not adequately
controlled by treatment with metformin alone at the onset of
treatment with the composition or combination of the present
invention.
[0086] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may be a patient suffering
from diabetes type 2, wherein diabetes type 2 is not adequately
controlled by treatment with insulin glargine alone, for example by
treatment with insulin glargine for at least 2 or at least 3
months. In particular, the diabetes type 2 is not adequately
controlled by treatment with insulin glargine alone at the onset of
treatment with the composition or combination of the present
invention.
[0087] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may be a patient suffering
from diabetes type 2, wherein diabetes type 2 is not adequately
controlled by treatment with lixisenatide alone, for example by
treatment with lixisenatide for at least 2 or at least 3 months. In
particular, the diabetes type 2 is not adequately controlled by
treatment with lixisenatide alone at the onset of treatment with
the composition or combination of the present invention.
[0088] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may be a patient suffering
from diabetes type 2, wherein diabetes type 2 is not adequately
controlled by treatment with at least one oral antidiabetic drug
and insulin glargine alone, such as metformin and insulin glargine
alone, or with at least one oral antidiabetic drug and lixisenatide
alone, such as metformin and lixisenatide alone, for example by
treatment for at least 2 or at least 3 months. In particular, the
diabetes type 2 is not adequately controlled by treatment with at
least one oral antidiabetic drug and insulin glargine alone, such
as metformin and insulin glargine alone, or with at least one oral
antidiabetic drug and lixisenatide alone, such as metformin and
lixisenatide alone at the onset of treatment with the composition
or combination of the present invention. The oral antidiabetic drug
may be selected from the group consisting of metformin,
sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors (sodium glucose
co-transporter 2 inhibitors) and glinides, and combinations
thereof. Preferred combinations comprise two of these oral
antidiabetics, for example metformin plus sulfonylurea, metformin
plus DPP-4 inhibitor, metformin plus glinide, metformin plus SGLT-2
inhibitor, sulfonylurea plus DPP-4 inhibitor.
[0089] The oral antidiabetic drug may be a single oral antidiabetic
drug, such as metformin only, sulfonylurea only, DPP-4 inhibitor
(dipeptidyl-peptidase 4 inhibitor) only, SGLT-2 inhibitor only, or
a glinide only.
[0090] In the present invention, a patient the diabetes type 2 of
which is not adequately controlled if at least one physiological
parameter describing blood glucose concentration (i.e. the HbA1c
value, the postprandial plasma glucose concentration, the
postprandial plasma glucose excursion, or/and the fasting plasma
glucose concentration) exceeds normoglycemic values, as described
herein. In particular, a patient the diabetes type 2 of which is
not adequately controlled may have
(i) a HbA1c value in the range of 7% to 10% or even larger, (ii) a
postprandial glucose excursion, in particular a 2-hour postprandial
glucose excursion, of at least 2 mmol/L, or even larger, (iii) a
postprandial plasma glucose concentration, in particular a 2-hour
postprandial glucose concentration, of at least 10 mmol/L, or even
larger, or/and (iv) a fasting plasma glucose of at least 7.0 mmol/L
or at least 8.0 mmol/L, or even larger.
[0091] Before onset of the treatment of the present invention, the
patient to be treated may have received at least one oral
antidiabetic drug (OAD), such as metformin, sulfonylurea, DPP-4
inhibitor, SGLT-2 inhibitor (sodium glucose co-transporter 2
inhibitor) or/and a glinide, optionally combined with lixisenatide
or insulin glargine. Before onset of the treatment of the present
invention, the patient to be treated may have received a
combination of at least two of these oral antidiabetics, for
example metformin plus sulfonylurea, metformin plus DPP-4
inhibitor, metformin plus glinide, metformin plus SGLT-2 inhibitor,
sulfonylurea plus DPP-4 inhibitor, optionally combined with
lixisenatide or insulin glargine. Before onset of the treatment of
the present invention, the patient to be treated may also have
received a single oral antidiabetic drug (OAD), such as metformin
only, sulfonylurea only, DPP-4 inhibitor (dipeptidyl-peptidase 4
inhibitor) only, SGLT-2 inhibitor only, or glinide only, optionally
combined with lixisenatide or insulin glargine. At the onset of the
treatment according to the present invention, the treatment with an
oral antidiabetic drug, especially an oral antidiabetic drug which
is not metformin, may be discontinued.
[0092] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may be an obese patient.
In the present invention, an obese patient may have a body mass
index of at least 30 kg/m.sup.2, at least 31 kg/m.sup.2, at least
32 kg/m.sup.2 or at least 33 kg/m.sup.2. Preferred is a body mass
index of at least 30 kg/m.sup.2 or at least 31 kg/m.sup.2.
[0093] The patient to be treated by the composition of the present
invention suffering from diabetes type 2 may have a normal body
weight. In the present invention, a patient having normal body
weight may have a body mass index in the range of 17 kg/m.sup.2 to
25 kg/m.sup.2, 17 kg/m.sup.2 to <30 kg/m.sup.2 or <30
kg/m.sup.2.
[0094] The patient to be treated by the composition of the present
invention may be an adult patient. The patient may have an age of
at least 18 years of may have an age in the range of 18 to 80
years, of 18 to 50 years, or 40 to 80 years, or 50 to 60 years, or
50 to 64 years, or 65 to 74 years, or at least 75 years. The
patient may be at least 50 years old. The patient may be younger
than 50 years.
[0095] The patient to be treated by the composition of the present
invention may be a patient who does not receive an antidiabetic
treatment, for instance by insulin or/and related compounds,
metformin or GLP-1 agonists such as lixisenatide, in particular at
the onset of the treatment of the present invention. In particular,
the patient to be treated does not receive a GLP-1 receptor agonist
(such as lixisenatide) or/and an insulin.
[0096] The patient to be treated by the composition of the present
invention may suffer from diabetes mellitus type 2 for at least 1
year or at least 2 years. In particular, in the diabetes type 2
patient, diabetes mellitus type 2 has been diagnosed at least 1
year or at least 2 years before onset of therapy by the composition
or combination of the present invention.
[0097] The diabetes type 2 patient may have a HbA.sub.1c value of
at least about 9%, at least 8.5%, at least 8%, at least about 7,5%,
or at least 7.0%, or the patient may have a HbA.sub.1c value of
about 7% to about 10%, in particular (I) when the patient is
treated with (a) metformin, a sulfonylurea, a DPP-4 inhibitor, an
SGLT-2 inhibitor or/and a glinide, or a combination thereof,
optionally with lixisenatide or insulin glargine, (b) metformin,
(c) metformin and lixisenatide, (d) insulin glargine, or (e)
metformin and insulin glargine alone, or (II) without an
antidiabetic treatment. In particular, these HbA1c values are
reached at the onset of the treatment with the composition or
combination of the present invention, or before such treatment, for
example within one month before such treatment. The combination of
oral antidiabetics may be a combination of at least two oral
antidiabetics, for example metformin plus sulfonylurea, metformin
plus DPP-4 inhibitor, metformin plus glinide, metformin plus SGLT-2
inhibitor, sulfonylurea plus DPP-4 inhibitor, optionally combined
with lixisenatide or insulin glargine. Preferred is a HbA.sub.1c
value of at least about 8% or at least about 8.5%.
[0098] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving the HbA.sub.1c value in a patient suffering from diabetes
type 2, as described herein.
[0099] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving glucose tolerance in a patient suffering from diabetes
type 2, as described herein.
[0100] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving postprandial plasma glucose concentration in a patient
suffering from diabetes type 2, as described herein.
[0101] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving postprandial plasma glucose excursion, in particular the
2-hour postprandial glucose excursion, in a patient suffering from
diabetes type 2, as described herein.
[0102] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving fasting plasma glucose concentration in a patient
suffering from diabetes type 2, as described herein.
[0103] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving average 7-point SMPG profile. Self-monitored plasma
glucose (SMPG)", as used herein, is in particular the "7-point Self
Monitored Plasma Glucose". "7-point Self Monitored Plasma Glucose"
in particular refers to the measurement of plasma glucose seven
times a day and calculation of the average plasma glucose
concentration therefrom. The "7-point Self Monitored Plasma
Glucose" value is in particular an average plasma glucose
concentration including fasting and postprandial conditions. In
particular, measurements of plasma glucose concentration are
performed pre-breakfast, post-breakfast (e.g. 2-hour
post-breakfast), pre-lunch, post-lunch (e.g. 2-hour post-lunch),
pre-dinner, post-dinner (e.g. 2-hour post-dinner) and at bed-time.
The treatment by the combination of the present invention, as
described herein, can improve the self-monitored plasma
glucose.
[0104] In yet another aspect of the present invention, the
composition or combination as described herein can be used for
improving body weight in a patient suffering from diabetes type 2,
as described herein.
[0105] In the present invention, normoglycemic values are blood
glucose concentrations of in particular 60-140 mg/dl (corresponding
to 3,3 bis 7.8 mM). This range refers in particular to blood
glucose concentrations under fasting conditions or/and postprandial
conditions.
[0106] The diabetes type 2 patient may have a postprandial plasma
glucose, in particular a 2-hour postprandial plasma glucose
concentration of at least 10 mmol/L, at least 12 mmol/L, at least
13 mmol/L, at least 14 mmol/L, at least 14.5 mmol/L, at least 15
mmol/L, at least 16 mmol/L, or at least 17 mmol/L, in particular
(I) when the patient is treated with (a) metformin, a sulfonylurea,
a DPP-4 inhibitor, an SGLT-2 inhibitor or/and a glinide, or a
combination thereof, optionally with lixisenatide or insulin
glargine, (b) metformin, (c) metformin and lixisenatide, (d)
insulin glargine, or (e) metformin and insulin glargine alone, or
(II) without an antidiabetic treatment. In particular, these plasma
glucose concentrations are reached at the onset of the treatment
with the composition or combination of the present invention, or
before such treatment, for example within one month before such
treatment. These plasma glucose concentrations exceed normoglycemic
concentrations. The combination of oral antidiabetics may be a
combination of at least two oral antidiabetics, for example
metformin plus sulfonylurea, metformin plus DPP-4 inhibitor,
metformin plus glinide, metformin plus SGLT-2 inhibitor,
sulfonylurea plus DPP-4 inhibitor, optionally combined with
lixisenatide or insulin glargine. Preferred is a postprandial
plasma glucose, in particular a 2-hour postprandial plasma glucose
concentration, of at least 14 mmol/L, at least 14.5 mmol/L or at
least 15 mmol/L.
[0107] The diabetes type 2 patient may have a glucose excursion (in
particular a 2-hour postprandial glucose excursion) of at least 2
mmol/L, at least 3 mmol/L, at least 4 mmol/L, at least 5 mmol/L, at
least 5.5 mmol/L, at least 6 mmol/L, at least 6.5 mmol/L, or at
least 7 mmol/L, in particular (I) when the patient is treated with
(a) metformin, a sulfonylurea, a DPP-4 inhibitor, an SGLT-2
inhibitor or/and a glinide, or a combination thereof, optionally
with lixisenatide or insulin glargine, (b) metformin, (c) metformin
and lixisenatide, (d) insulin glargine, or (e) metformin and
insulin glargine alone, or (II) without an antidiabetic treatment.
In particular, these plasma glucose excursions are reached at the
onset of the treatment with the composition or combination of the
present invention, or before such treatment, for example within one
month before such treatment. These plasma glucose excursions exceed
normoglycemic conditions. The combination of oral antidiabetics may
be a combination of at least two oral antidiabetics, for example
metformin plus sulfonylurea, metformin plus DPP-4 inhibitor,
metformin plus glinide, metformin plus SGLT-2 inhibitor,
sulfonylurea plus DPP-4 inhibitor, optionally combined with
lixisenatide or insulin glargine. Preferred is a glucose excursion
of at least 5 mmol/L or at least 7 mmol/L.
[0108] In the present invention, the glucose excursion is in
particular the difference of the 2-hour postprandial plasma glucose
concentration and the plasma glucose concentration 30 minutes prior
to a meal test (2-hour postprandial glucose excursion). In the
present invention, the glucose excursion may also be calculated as
the difference of the 30-min or 1-hour postprandial plasma glucose
concentration and the plasma glucose concentration 30 minutes prior
to a meal test (30-min or 1-hour postprandial glucose excursion).
It is preferred that the glucose excursion is a 2-hour postprandial
glucose excursion.
[0109] "Postprandial" is a term that is well known to a person
skilled in the art of diabetology. The term "postprandial"
describes in particular the phase after a meal or/and exposure to
glucose under experimental conditions. In a healthy person this
phase is characterised by an increase and subsequent decrease in
blood glucose concentration. The term "postprandial" or
"postprandial phase" typically ends up to 2 h after the ingestion
of a meal or/and exposure to glucose. In the present invention, the
term "postprandial plasma glucose" is in particular a 30-min,
1-hour or 2-hour postprandial plasma glucose, i.e. a postprandial
plasma glucose determined 30 min, 1 hour or 2 hours after the
ingestion of a meal or/and exposure to glucose. In particular, the
postprandial plasma glucose concentration is a 2-hour postprandial
plasma glucose concentration.
[0110] The diabetes type 2 patient as disclosed herein may have a
fasting plasma glucose concentration of at least 7 mmol/L, at least
8 mmol/L, at least 9 mmol/L, at least 9.5 mmol/L, at least 10
mmol/L, or at least 11 mmol/L, in particular (I) when the patient
is treated with (a) metformin, a sulfonylurea, a DPP-4 inhibitor,
an SGLT-2 inhibitor or/and a glinide, or a combination thereof,
optionally with lixisenatide or insulin glargine, (b) metformin,
(b) metformin and lixisenatide, (c) insulin glargin, or (d)
metformin and insulin glargine alone, or (II) without an
antidiabetic treatment. In particular, these plasma glucose
concentrations are reached at the onset of the treatment with the
composition or combination of the present invention, or before such
treatment, for example within one month before such treatment.
These fasting plasma glucose concentrations exceed normoglycemic
concentrations. The combination of oral antidiabetics may be a
combination of at least two oral antidiabetics, for example
metformin plus sulfonylurea, metformin plus DPP-4 inhibitor,
metformin plus glinide, metformin plus SGLT-2 inhibitor,
sulfonylurea plus DPP-4 inhibitor, optionally combined with
lixisenatide or insulin glargine. Preferred is a fasting plasma
glucose concentration of at least 7 mmol/L, at least 9 mmol/L or at
least 9.5 mmol/L.
[0111] The diabetes type 2 patient as disclosed herein may have a
self-monitored plasma glucose concentration of at least 8 mmol/L,
at least 9 mmol/L, at least 10 mmol/L, or at least 11 mmol/L, in
particular when the patient is treated with (a) metformin, a
sulfonylurea, a DPP-4 inhibitor, an SGLT-2 inhibitor or/and a
glinide, or a combination thereof, optionally with lixisenatide or
insulin glargine, (b) metformin, (c) metformin and lixisenatide,
(d) insulin glargine, or (e) metformin and insulin glargine alone,
or (II) without an antidiabetic treatment. In particular, these
plasma glucose concentrations are reached at the onset of the
treatment with the composition or combination of the present
invention, or before such treatment, for example within one month
before such treatment. These plasma glucose concentrations exceed
normoglycemic concentrations. The combination of oral antidiabetics
may be a combination of at least two oral antidiabetics, for
example metformin plus sulfonylurea, metformin plus DPP-4
inhibitor, metformin plus glinide, metformin plus SGLT-2 inhibitor,
sulfonylurea plus DPP-4 inhibitor, optionally combined with
lixisenatide or insulin glargine. Preferred is a self-monitored
plasma glucose concentration of at least 9 mmol/L or at least 10
mmol/L.
[0112] In the present invention, the composition as described
herein may be administered to a patient in need thereof, in an
amount sufficient to induce a therapeutic effect.
[0113] In the present invention, the composition as described
herein may comprise at least one of suitable pharmaceutically
acceptable carriers, adjuvants, or/and auxiliary substances.
[0114] The composition as described herein may be administered
parenterally, e.g. by injection (such as by intramuscular or by
subcutaneous injection). Suitable injection devices, for instance
the so-called "pens" comprising a cartridge comprising the active
ingredient, and an injection needle, are known.
[0115] The pharmaceutical composition as described herein can be
provided within a container, for example an ampoule, a vial or a
"pen", as described herein, to be used by the patient. For example,
the pharmaceutical composition being a liquid formulation can be
provided within a vial. From such vial, the patient can draw up the
required dose into a syringe (in particular a single-use syringe).
In particular, the combination of the present invention can be
provided in a pen.
[0116] The dosage of the composition as described herein may be
determined by one of the active agents of the composition to be
administered, i.e. by the amount of insulin glargine or by the
amount of lixisenatide. It is contemplated that in this case, the
second active agent of the composition is administered in an amount
defined by the fixed-dose ratio of the composition.
[0117] The dose of the composition as described herein may be
determined by the amount of lixisenatide to be administered.
[0118] In the present invention, the composition or combination as
described herein may be administered in an amount in the range of
10 to 15 .mu.g lixisenatide per dose or 15 to 20 .mu.g lixisenatide
per dose.
[0119] In the present invention, the composition or combination as
described herein may be administered in a daily dose in the range
of 10 to 20 .mu.g lixisenatide, in the range of 10 to 15 .mu.g
lixisenatide, or in the range of 15 to 20 .mu.g lixisenatide.
[0120] The composition as described herein may be administered by
one injection per day.
[0121] The pharmaceutical composition as described herein may be
administered in a dose of 0.05 to 0.5 .mu.g/kg body weight
lixisenatide.
[0122] The dose of the composition of the present invention may
also be determined by the amount of insulin glargine required. For
example, the insulin glargine dose to be injected may be 40 U or
less, or in a range from 10 to 40 U insulin glargine or 20 U to 40
U insulin glargine. The insulin glargine dose to be injected may
also be 60 U or less, or in a range from 10 U to 60 U insulin
glargine or 30 U to 60 U insulin glargine. The daily insulin
glargine dose to be injected may be 40 U or less, or in a range
from 10 to 40 U insulin glargine or 20 U to 40 U insulin glargine.
The daily insulin glargine dose to be injected also may be 60 U or
less, or in a range from 10 U to 60 U insulin glargine or 30 U to
60 U insulin glargine.
[0123] The composition of the present invention may be administered
in a dose of 0.25 to 1.5 U/kg body weight insulin glargine.
[0124] In the present invention, the composition as described
herein may be a liquid composition. The skilled person knows liquid
compositions of lixisenatide suitable for parenteral
administration. The skilled person also knows liquid compositions
of insulin glargine suitable for parenteral administration. A
liquid composition of the present invention may have an acidic or a
physiologic pH. An acidic pH preferably is in the range of pH
1-6.8, pH 3.5-6.8, or pH 3.5-5. A physiologic pH preferably is in
the range of pH 2.5-8.5, pH 4.0-8.5, or pH 6.0-8.5. The pH may be
adjusted by a pharmaceutically acceptable diluted acid (typically
HCl) or pharmaceutically acceptable diluted base (typically
NaOH).
[0125] The liquid composition of the present invention may comprise
a suitable preservative. A suitable preservative may be selected
from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid
ester. A preferred preservative is m-cresol.
[0126] The liquid composition of the present invention may comprise
a tonicity agent. A suitable tonicity agent may be selected from
glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or
magnesium containing compounds such as CaCl.sub.2. The
concentration of glycerol, lactose, sorbitol, mannitol and glucose
may be in the range of 100-250 mM. The concentration of NaCl may be
up to 150 mM. A preferred tonicity agent is glycerol.
[0127] The liquid composition of the present invention may comprise
methionine from 0.5 .mu.g/mL to 20 .mu.g/mL, preferably from 1
.mu.g/ml to 5 .mu.g/ml. Preferably, the liquid composition
comprises L-methionine.
[0128] Yet another aspect of the present invention refers to a
method of treatment of a medical indication, disease or condition,
as described herein. For example, the method may comprise the
administration of the composition as described herein. The method
may be a method of treatment of diabetes type 2 patients, or/and of
treatment of conditions associated with diabetes type 2, as
described herein. The patient may be a patient as defined
herein.
[0129] A further aspect of the present invention is a method for
improvement of glycemic control in diabetes type 2 patients, said
method comprising administering the composition of the present
invention to a patient in need thereof. In the method of the
present invention, the patient may be the patient defined
herein.
[0130] Yet another aspect of the present invention refers to the
use of the composition as described herein for the manufacture of a
composition for the treatment of a medical indication, disease or
condition, as described herein. For example, the composition of the
present invention can be used for the manufacture of a composition
for the treatment of diabetes type 2 patients, or/and for the
treatment of conditions associated with diabetes type 2. In
particular, the composition of the present invention can be used
for the manufacture of a composition for the improvement of
glycemic control, improvement of glucose tolerance, improvement of
postprandial plasma glucose concentration, improvement of
postprandial plasma glucose excursion, improvement of fasting
plasma glucose concentration, or/and improvement of the HbA.sub.1c
value. The patient may be a patient as defined herein.
[0131] Yet another aspect of the present invention relates to the
use of a combination as described herein for the preparation of
medicament for the treatment of a medical indication, disease or
condition, as described herein, in particular of diabetes mellitus
type 1 or/and 2.
[0132] Yet another aspect of the present invention relates to the
combination as described herein for use in the treatment of a
medical indication, disease or condition, as described herein, in
particular for use in the treatment of diabetes mellitus type 1
or/and 2.
[0133] Yet another aspect of the present invention is a method of
treatment of diabetes mellitus type 1 or/and 2, comprising
administering
[0134] (I) a pharmaceutical composition comprising [0135]
Lixisenatide (desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2)
or/and a pharmaceutically acceptable salt thereof, and [0136]
insulin glargine or/and a pharmaceutically acceptable salt thereof,
[0137] wherein the compound (b) and compound (a) are present in a
ratio of about 1.6 to about 2.4 U of compound (b) per .mu.g of
compound (a), or/and
[0138] (II) a pharmaceutical composition comprising [0139]
Lixisenatide (desPro.sup.36Exendin-4(1-39)-Lys.sub.6-NH.sub.2)
or/and a pharmaceutically acceptable salt thereof, and [0140]
insulin glargine or/and a pharmaceutically acceptable salt
thereof,
[0141] wherein the compound (b) and compound (a) are present in a
ratio of about 2.6 to about 3.4 U of compound (b) per .mu.g of
compound (a).
[0142] In this method, the specific compositions as described
herein, being covered by composition (I) or/and (II), can be
used.
[0143] The patient to be treated by this method may be any patient
as described herein.
[0144] In particular, in the method of the present invention,
composition (I) or composition (II) is administered.
[0145] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a dose of insulin glargine of less than or equal to 40 U,
and the pharmaceutical composition of (II) can be administered if
the diabetes mellitus type 1 or/and 2 patient requires a dose of
insulin glargine of more than 40 U.
[0146] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a dose of insulin glargine in the range of 10 to 40 U, and
the pharmaceutical composition of (II) can be administered if the
diabetes mellitus type 1 or/and 2 patient requires a dose of
insulin glargine in the range of more than 40 U up to 60 U.
[0147] By this method, over-dosing of lixisenatide or/and insulin
glargine can be avoided. In particular, over-dosing of lixisenatide
can be avoided. If composition (I) is administered, the
lixisenatide dose can be in the range of about 15.4 to about 25
.mu.g, or about 16.7 to about 25 .mu.g, or a range as described
herein, when a dose of 40 U of insulin glargine is administered. If
composition (II) is administered, the lixisenatide dose can be in
the range of about 17.6 to about 23.1 .mu.g, or a range as
described herein, when a dose of 60 U of insulin glargine is
administered.
[0148] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a dose of insulin glargine of less than or equal to 30 U,
and the pharmaceutical composition of (II) can be administered if
the diabetes mellitus type 1 or/and 2 patient requires a dose of
insulin glargine of more than 30 U.
[0149] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a dose of insulin glargine in the range of 10 to 30 U, and
the pharmaceutical composition of (II) can be administered if the
diabetes mellitus type 1 or/and 2 patient requires a dose of
insulin glargine in the range of more than 30 U up to 60 U.
[0150] In this method, the insulin glargine dose is in particular a
daily dose of insulin glargine.
[0151] In this method, the lixisenatide dose is in particular a
daily dose of lixisenatide.
[0152] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine of less than or equal to
40 U, and the pharmaceutical composition of (II) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine of more than 40 U.
[0153] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine in the range of 10 to 40
U, and the pharmaceutical composition of (II) can be administered
if the diabetes mellitus type 1 or/and 2 patient requires a daily
dose of insulin glargine in the range of more than 40 U up to 60
U.
[0154] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine of less than or equal to
30 U, and the pharmaceutical composition of (II) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine of more than 30 U.
[0155] In this method, the pharmaceutical composition of (I) can be
administered if the diabetes mellitus type 1 or/and 2 patient
requires a daily dose of insulin glargine in the range of 10 to 30
U, and the pharmaceutical composition of (II) can be administered
if the diabetes mellitus type 1 or/and 2 patient requires a daily
dose of insulin glargine in the range of more than 30 U up to 60
U.
[0156] In this method, the patient to be treated can be a patient
as defined herein.
[0157] The invention is further illustrated by the following
figures and examples.
BRIEF DESCRIPTION OF THE DRAWINGS
[0158] FIG. 1--Mean HbA1c (%) by visit--mITT population.
S=Screening (Week -6), R=Run-in (Week -1), B=Baseline, LOCF=Last
observation carried forward. INS/LIXI=fixed ratio combination,
INS=Insulin Glargine, LIXI=Lixisenatide. Note: The plot included
all scheduled measurements obtained during the study, including
those obtained after IMP discontinuation or introduction of rescue
medication.
[0159] FIG. 2--Mean change in HbA1c (%) from baseline by
visit--mITT population. B=Baseline, LOCF=Last observation carried
forward. INS/LIXI=fixed ratio combination, INS=Insulin Glargine,
LIXI=Lixisenatide. Note: The plot included all scheduled
measurements obtained during the study, including those obtained
after IMP discontinuation or introduction of rescue medication.
[0160] FIG. 3--Mean body weight (kg). B=Baseline, LOCF=Last
observation carried forward. INS/LIXI=fixed ratio combination,
INS=Insulin Glargine, LIXI=Lixisenatide. The analysis included all
scheduled measurements obtained during the study, including those
obtained after IMP discontinuation or introduction of rescue
therapy.
[0161] FIG. 4--Mean fasting plasma glucose (mmol/L/[mg/dL]) by
visit--mITT population. S=Screening (Week -6), R=Run-in (Week -1),
B=Baseline, LOCF=Last observation carried forward. INS/LIXI=fixed
ratio combination, INS=Insulin Glargine, LIXI=Lixisenatide. The
analysis included all scheduled measurements obtained during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy.
[0162] FIG. 5--Mean fasting plasma glucose (mmol/L/[mg/dL]) from
baseline by visit--mITT population. B=Baseline, LOCF=Last
observation carried forward. INS/LIXI=fixed ratio combination,
INS=Insulin Glargine, LIXI=Lixisenatide. The analysis included all
scheduled measurements obtained during the study, including those
obtained after IMP discontinuation or introduction of rescue
therapy.
[0163] FIG. 6--Mean 7-point SMPG (mmol/L/[mg/dL]) at baseline and
Week 30. SMPG=Self-monitored plasma glucose. INS/LIXI=Fixed Ratio
Combination, INS=Insulin Glargine, LIXI=Lixisenatide. The analysis
included all scheduled measurements obtained during the study,
including those obtained after IMP discontinuation or introduction
of rescue therapy.
[0164] FIG. 7--Mean average daily insulin glargine dose (U) by
visit. LOCF=Last observation carried forward. INS/LIXI=fixed ratio
combination, INS=Insulin Glargine, LIXI=Lixisenatide. The analysis
included scheduled measurements obtained up to the date of last
injection of the IMP, including those obtained after introduction
of rescue therapy.
[0165] FIG. 8--Graphical Study Design.
[0166] FIG. 9--Plot of mean HbA1c (%) by visit--mITT population.
S=Screening (Week -8), R=Run-in (Week -1), B=Baseline, LOCF=Last
observation carried forward. INS/LIXI=Fixed Ratio Combination,
INS=Insulin Glargine. Note: The plot included all scheduled
measurements obtained during the study, including those obtained
after IMP discontinuation or introduction of rescue medication.
[0167] FIG. 10--Plot of mean change in HbA1c (%) from baseline by
visit--mITT population. B=Baseline, LOCF=Last observation carried
forward. INS/LIXI=Fixed Ratio Combination, INS=Insulin Glargine.
Note: The plot included all scheduled measurements obtained during
the study, including those obtained after IMP discontinuation or
introduction of rescue medication.
[0168] FIG. 11--Plot of mean change in body weight (kg) from
baseline by visit--mITT population. B=Baseline, LOCF=Last
observation carried forward. INS/LIXI=Fixed Ratio Combination,
INS=Insulin Glargine. The analysis included all scheduled
measurements obtained during the study, including those obtained
after IMP discontinuation or introduction of rescue therapy.
[0169] FIG. 12--Plot of mean 7-point SMPG at baseline and Week
30--mITT population. SMPG=Self-monitored plasma glucose.
INS/LIXI=Fixed Ratio Combination, INS=Insulin Glargine. The
analysis included all scheduled measurements obtained during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy.
[0170] FIG. 13--Plot of mean daily insulin glargine dose (U) by
visit--mITT population. Week-6=First week of run-in, B=Baseline,
LOCF=Last observation carried forward. INS/LIXI=Fixed Ratio
Combination, INS=Insulin Glargine. The analysis included scheduled
measurements obtained up to the date of last injection of the IMP,
including those obtained after introduction of rescue therapy.
[0171] FIG. 14--Plot of mean fasting plasma glucose by visit--mITT
population. S=Screening (Week -8), R=Run-in (Week -1), B=Baseline,
LOCF=Last observation carried forward. INS/LIXI=Fixed Ratio
Combination, INS=Insulin Glargine. The analysis included all
scheduled measurements obtained during the study, including those
obtained after IMP discontinuation or introduction of rescue
therapy.
[0172] FIG. 15 shows the graphical study design of Example 1.
[0173] FIG. 16 shows the printing on the number sleeve (top) and
the detailed doses (bottom) of Pen A and Pen B.
[0174] FIG. 17 shows the follow-up guidance for neutropenia.
[0175] FIG. 18 shows the follow-up guidance for
thrombocytopenia.
[0176] FIG. 19 shows the follow-up guidance for increase in
ALT.
[0177] FIG. 20 shows the follow-up guidance for acute renal
failure.
[0178] FIG. 21 shows the follow-up guidance for suspicion of
rhabdomyolysis.
[0179] FIG. 22 shows the back-up plan for SAE and other
Investigator Expedited Events reporting process when the e-CRF
system fails.
[0180] FIG. 23 shows questions 1-3 of the Treatment-Related Impact
Measure for Diabetes (TRIM-D) questionnaire.
[0181] FIG. 24 shows questions 4-6 of the Treatment-Related Impact
Measure for Diabetes (TRIM-D) questionnaire.
[0182] FIG. 25 shows question 7 of the Treatment-Related Impact
Measure for Diabetes (TRIM-D) questionnaire.
[0183] FIG. 26 shows page 1 of the EuroQoL Five Dimension (EQ-5D)
questionnaire.
[0184] FIG. 27 shows page 2 of the EuroQoL Five Dimension (EQ-5D)
questionnaire.
[0185] FIG. 28 shows page 1 of the Impact of Weight on Quality of
Life-Lite (IWQOL-Lite) questionnaire.
[0186] FIG. 29 shows page 2 of the Impact of Weight on Quality of
Life-Lite (IWQOL-Lite) questionnaire.
EXAMPLE 1
[0187] A randomized, 30-week, active-controlled, open label, 2
treatment-arm, parallel-group, multicenter study comparing the
efficacy and safety of the insulin glargine/lixisenatide fixed
ratio combination to insulin glargine with or without metformin in
patients with Type 2 Diabetes Mellitus.
[0188] Clinical Trial Summary
TABLE-US-00002 COMPOUND:HOE901 (insulin glargine)/AVE0010
(lixisenatide) combination TITLE A randomized, 30-week,
active-controlled, open label, 2 treatment- arm, parallel-group,
multicenter study comparing the efficacy and safety of the insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
with or without metformin in patients with T2DM INVESTIGATOR/TRIAL
Multinational LOCATION PHASE OF Phase III DEVELOPMENT STUDY
OBJECTIVE(S) Primary Objective To demonstrate over 30 weeks the
superiority on HbA.sub.1c reduction of the insulin
glargine/lixisenatide fixed ratio combination versus insulin
glargine in type 2 diabetic patients with or without metformin.
Secondary Objective(s) To assess over 30 weeks the effects of the
insulin glargine/lixisenatide fixed ratio combination versus
insulin glargine on: Percentage of patients reaching HbA.sub.1c
targets; Glycemic control in relation to a meal as evaluated by
glucose excursion and 2-hour Post-prandial Plasma Glucose (PPG)
during a standardized meal test; Body weight; 7-point
Self-Monitored Plasma Glucose (SMPG) profile; Percentage of
patients reaching HbA.sub.1c targets with no body weight gain
and/or documented symptomatic hypoglycemia; Insulin glargine dose;
Fasting Plasma Glucose (FPG) To assess the safety and tolerability
in each treatment group. To assess the development of anti-insulin
antibodies and anti- lixisenatide antibodies (fixed ratio
combination treatment group for the latter). To assess the total
and active plasma concentration of lixisenatide before and
following injection (fixed ratio combination treatment group). To
assess the treatment effects of each treatment group on Patient
Reported Outcomes (PROs) measured by the following questionnaires:
Treatment related impact measure--diabetes (TRIM-D) EudoQol-5D
(EQ-5D) Impact of Weight on Quality of Life-Lite (IWQoL-Lite) To
assess patient's overall response to treatment for each treatment
group using patient- and physician-rated global treatment
effectiveness evaluation scales STUDY DESIGN Open-label, 1:1
randomized, active-controlled, 2-arm, 30-week treatment duration,
parallel-group multinational and multicenter study comparing the
insulin glargine/lixisenatide fixed ratio combination to insulin
glargine. The randomization will be stratified by value of
HbA.sub.1c at visit 5 (week-1) (<8%, .gtoreq.8%) and metformin
use at screening (Y,N). The study will comprise 3 periods: An up-to
8-week screening period, which includes An up to 2-week screening
phase: Run-in visit can be performed less than 2 weeks after
screening visit if the laboratory data are available. A 6-week
run-in phase: Switching to (if appropriate) and/or dose
optimization of insulin glargine, continuing metformin (if
appropriate) and stopping sulfonylurea(SU), glinide, sodium-glucose
co- transporter 2 inhibitor (SGLT-2i) or dipeptidyl- peptidase-4
inhibitor (DPP-4i) if previously taken at V2. A 30-week open-label
randomized treatment period At the end of the screening period,
patients whose HbA.sub.1c is .gtoreq. 7% and .ltoreq. 10%, whose
mean fasting SMPG calculated from the self-measurements for the 7
days prior to randomization visit is .ltoreq. 140 mg/dL (7.8
mmol/L) and whose insulin glargine daily dose is .gtoreq. 20 u or
.ltoreq. 50 U, will enter a 30-week, open-label randomized
treatment period comparing lixisenatide/insulin glargine fixed
ratio combination to insulin glargine (.+-.metformin for both
treatments). A 3-day post-treatment safety follow-up period for all
the patients after permanent IMP discontinuation (except for
patients who prematurely discontinue the study treatment; those
patients should continue in the study up to the scheduled date of
study completion). STUDY Inclusion Criteria: POPULATION Patients
with type 2 diabetes mellitus diagnose at least 1 Main Selection
year before the screening visit. Criteria Patients who have been
treated with basal insulin for at least 6 months before the
screening visit. Patients who have been treated for at least 3
months prior to the screening visit, with a stable basal insulin
regimen (i.e. type of insulin and time/frequency of the injection).
The total daily basal insulin dose should be stable (.+-.20%) and
between 15 and 40 U/day for at least 2 months prior to the
screening visit. Patients who have been treated with basal insulin
alone or in combination with a stable dose for at least 3 months
before the screening visit of 1 to 2 OADs that can be: metformin
(.gtoreq.1500 mg/day or maximal tolerated dose), a sulfonylurea, a
glinide, a dipeptidyl-peptidase-4 inhibitor or a SGLT-2 inhibitor.
Patients with FPG .ltoreq. 180 mg/dL (10.0 mmol/L) at screening
visit. Signed written informed consent. Exclusion Criteria: Age
under legal age of adulthood at screening visit. HbA1c at screening
visit < 7.5% and > 10%. Pregnancy of lactation, women of
childbearing potential with no effective contraceptive method. Use
of other oral or injectable glucose-lowering agents than stated in
the inclusion criteria in a period of 3 months prior to screening.
Previous use of insulin regimen other than basal insulin (e.g.
prandial or pre-mixed insulin) more than 3 months ago. Note: Short
term treatment due to intercurrent illness including gestational
diabetes is allowed at the discretion of the investigator
Discontinuation of a previous treatment with GLP-1 RAs due to
safety/tolerability issue or lack of efficacy. Laboratory findings
at the screening visit, including: Amylase and/or lipase > 3
times the upper limit of the normal laboratory range (ULN); ALT or
AST > 3 ULN; Calcitonin .gtoreq. 20 pg/ml (5.9 pmol/L); Positive
pregnancy test. Any contraindication to metformin use, according to
local labeling. (e.g. renal impairment defined as creatinine >
1.4 mg/dL in women, > 1.5 mg/dL in men, or creatinine clearance
< 60 mL/min, etc.) if the patient is taking metformin. Patient
who has a renal function impairment with creatinine clearance <
30 mL/min (using the Cockroft and Gault formula) or end-stage renal
disease for patients not treated with metformin. Contraindication
to use of insulin glargine, or lixisenatide. History of
hypersensitivity to insulin glargine, lixisenatide or to any of the
excipients. History of allergic reaction to any GLP-1 RA or insulin
glargine or to metacresol. Personal or immediate family history of
medullary thyroid cancer (MTC) or genetic condition that
predisposes to MTC (e.g. multiple endocrine neoplasia syndromes).
History of pancreatitis (unless pancreatitis was related to
gallstones and cholecystectomy was already performed), chronic
pancreatitis, pancreatitis during a previous treatment with
incretin therapies, pancreatectomy, stomach/gastric surgery.
Exclusion criteria for randomization at the end of the screening
period: HbA.sub.1c < 7% or > 10% at visit 5 (week-1). Mean
fasting SMPG calculated from the self-measurements for 7 days the
week before randomization visit (V6) is > 140 mg/dL (7.8
mmol/L). Average insulin glargine daily dose < 20 U or > 50 U
calculated for the last 3 days the week before visit 6. Amylase
and/or lipase > 3 ULN at visit 5 (week-1). Total expected
Approximately 700 randomized patents (350 per arm). number of
patients STUDY TREATMENTS(s) Investigational Tested drug: medicinal
product(s): Insulin glargine/lixisenatide fixed ratio combination
Formulation Insulin glargine/lixisenatide fixed ratio combination
is supplied as a sterile aqueous solution in a pre-filled
disposable SoloStar .RTM. pen- injector (100 U/mL insulin glargine
with 33 or 50 .mu.g/mL lixisenatide depending on the pen)
Pen-injector devices: The combination product will be
self-administered with a pre-filled disposable SoloStar .RTM.
pen-injector. The dose of the combination will be titrated
depending on the insulin glargine needs of the patient. Only the
insulin glargine dose appears in the pen dosing window. The dose
(.mu.g) of lixisenatide does not appear in the dose window although
lixisenatide is pre-mixed in the cartage. The lixisenatide dose is
increased or decreased concomitantly with any insulin glargine dose
change and also depends on the insulin glargine/lixisenatide fixed
ratio of the combination product. Two pens with different insulin
glargine/lixisenatide fixed ratios will be used to allow insulin
glargine titration from 10 to 60 U while limiting lixisenatide dose
to a maximum of 20 .mu.g/day: Pen A (yellow label, yellow dose
button): pre-filled disposable SoloStar .RTM. pen-injector
containing 3 ml of sterile solution of 100 U/mL insulin glargine
and 50 .mu.g/mL lixisenatide in ratio of 2:1 (2 units of insulin
glargine per 1 .mu.g lixisenatide). This pen allows administration
of daily combination doses between 10 U/5 .mu.g and 40 U/20 .mu.g.
Pen B (red label, red dose button): pre-filed disposable SoloStar
.RTM. pen-injector containing 3 ml of sterile solution of 100 U/mL
insulin glargine and 33 .mu.g/mL lixisenatide in ratio of 3:1 (3
units of insulin glargine per 1 .mu.g lixisenatide). This pen
allows administration of daily combination doses between 30 U/10
.mu.g and 60 U/20 .mu.g. It is intended mainly to be used for
patients requiring insulin glargine daily doses between 40 and 60
U. However, it may also be used for insulin glargine daily doses
between 30 and 40 U either at initiation of treatment (See below)
or during the treatment phase to allow dose decrease e.g. in case
of hypoglycemia without necessitating a return to pen A. Patients
who started treatment with Pen A and require a daily dose of
insulin glargine above 40 U will be switched to Pen B. Control
drug: Insulin glargine (Lantus .RTM.) Insulin glargine is supplied
as a sterile aqueous solution, in a pre- filled disposable SoloStar
.RTM. pen-injector (100 U/mL insulin glargine). Pen-injector
device: The pre-filled disposable SoloStar .RTM. pen-injector is
specifically labeled for the use in the study and contains in total
300 units/3 ml of insulin glargine. Disposable pre-filled
pen-injectors Lantus .RTM. SoloSTAR .RTM. are provided to all
patients at V2 and to patients randomized in the insulin glargine
arm at V6 (week 0, Day 1) and thereafter for the IMP injection.
Route(s) of Subcutaneous injector for both IMPs administration Dose
regimen During run-in phase: Starting dose of insulin glargine From
the star of run-in (visit 2), the only basal insulin allowed is
insulin glargine. Patients receiving any basal insulin other than
insulin glargine before screening will switch to once daily insulin
glargine at the start of visit 2. The initial dose of insulin
glargine will be the dose of previous basal insulin if they were
receiving 1 daily injection or the total daily dose of precious
insulin minus 20% if they were receiving more than 1 daily
injection. Patients receiving insulin glargine prior to the study
will start run-in at their pre-study dose level. Insulin glargine
can be injected at any time of the day but at the same time every
day. The time of the once daily injection is at the discretion of
the patient and investigator and will be fixed at the time of Visit
2 and should remain approximately the same throughout the study
(during run-in phase for all patients and also during the
randomized treatment period for patients randomized to the insulin
glargine treatment group). Adjustment of insulin glargine dose
During run-in phase, doses will be adjusted based on daily measured
fasting SMPG with the goal of improving fasting glycemic control
and allowing patients to meet the randomization criteria (HbA1c at
visit 5 .gtoreq. 7% and .ltoreq. 10%; mean fasting SMPG .ltoreq.
140 mg/dL [7.8 mmol/L] measured for 7 days the week before visit
6). The titration procedure to reach these criteria while avoiding
hypoglycemia is left at the discretion of the investigator. Small
decreases of dose are permitted in case of hypoglycemia, at the
discretion of the investigator. During open-label randomized
treatment period: Insulin glargine/lixisenatide fixed ratio
combination group Patients who received insulin glargine (Lantus
.RTM.) in the morning during the run-in phase: Patients having the
day before Visit 6 (D-1) a daily insulin glargine dose of <30 U
will start the combination treatment with pen A at a dose of 20 U
of insulin glargine/10 .mu.g of lixisenatide .gtoreq.30 U will
start the combination treatment with pen B at a
dose of 30 U of insulin glargine/10 .mu.g of lixisenatide. First
injection will be done on site morning of the randomization.
Patients who received insulin glargine at another time of the day
than morning during the run-in phase Patients will have to switch
to an administration within one hour prior to breakfast. A
procedure for transitioning time administration is offered below,
alternated changeover regimens may be employed if desired: The
morning of the baseline visit (D1) after randomization: injection
while patient is on site, of an insulin glargine dose equal to
1/2-2/3 (to be decided by the investigator) of the dose injected
the day prior to randomization (D-1) The next morning (D2),
patients having the day before Visit 6 (D-1) a daily insulin
glargine dose of <30 U will start the combination treatment with
pen A at a dose of 20 U of insulin glargine/10 .mu.g of
lixisenatide .gtoreq.30 U will start the combination treatment with
pen B at a dose of 30 U of insulin glargine/10 .mu.g of
lixisenatide. For all patients this first dose (either 20 U/10
.mu.g or 30 U/10 .mu.g) will be maintained stable for 2 weeks. For
two additional weeks, dose increase, if necessary, will be limited
to a maximum increase of +2 U and not more often than once a week.
After the first 4 weeks, the doses will be titrated once a week
according to the algorithm described in table below to achieve
glycemic targets (Fasting SMPG in the range of 80 to 100 mg/dL [4.4
to 5.6 mmol/L]) without hypoglycemia. Thereafter, until the end of
the study, the dose will be adjusted as necessary to maintain these
fasting SMPG targets. Dose adjustment algorithm Median of fasting
SMPG values from Insulin glargine dose preceding 3 days adjustments
(U/day) >140 mg/dL (>7.8 mmol/L) +4 >100 and .ltoreq.140
mg/dL (>5.6 and .ltoreq.7.8 mmol/L) +2 Glycemic target: 80 and
100 mg/dL (4.4 and No change 5.6 mmol/L), inclusive .gtoreq.60 and
<80 mg/dL (.gtoreq.3.3 and <4.4 mmol/L) -2 <60 mg/dL
(<3.3 mmol/L) or occurrence of 2 -2 to -4 or at the discretion
(or more) symptomatic hypoglycemic episodes of the investigator or
one severe hypoglycemic episode (requiring or medically qualified
assistance) documented in the preceding designee week. Insulin
glargine (Lantus .RTM.) group Patients who are randomized to
insulin glargine group will administer the day of randomization the
same daily dose of insulin glargine as the day prior to
randomization visit, and then continue the insulin dose titration
as necessary during the open-label randomized treatment period.
Time injection time should remain the same as the one determined at
visit 2 and used during the run-in phase. Dose will be adjusted
weekly following the same algorithm described above for the fixed
ratio combination. In both treatment groups Dose changes are based
on a median of fasting SMPG values from last 3 days measured by the
patient using glucometers and accessories supplied by the sponsor
for this study. Doses may be reduced or modified at any time for
hypoglycemia and according to the best clinical judgment of
investigator. The total daily insulin glargine dose will be capped
at 60 U. In case a dose > 60 U of insulin glargine is needed to
maintain HbA1c below predefined thresholds value, the dose should
be kept at 60 U and a recue therapy should be introduced (See
Section on Rescue Therapy below). All assessments planned at the
end of treatment visit are to be performed before initiating recue
therapy. Noninvestigational Background treatment metformin
(commercial metformin tablet) and medicial product(s)/(if rescue
therapy will be considered as NIMP(s) applicable) Formulation
Route(s) of Oral administration for metformin administration Dose
regimen Background therapy metformin (if appropriate) should be
administered according to local product labeling. If patients are
on metformin, if should be at a stable dose of at least 1500 mg/day
or maximal tolerated dose for at least 3 months prior to screening.
This should be continued and the dose should remain stable
throughout the study unless there is a specific safety issue
related to this treatment. Sulfonylureas, glinides, SGLT-2
inhibitors and DPP-4 inhibitors, if previously taken, will be
stopped at the start of run-in (Visit 2). Rescue Therapy Routine
fasting SMPG and central laboratory alerts on FPG and HbA1c are
required to ensure that glycemic parameter results remain under
predefined thresholds values. In the event that FPG/HbA1c exceed
the threshold values (see Section 7.4), if no reason can be found
for insufficient glucose control, or if appropriate actions fail or
if a dose > 60 U as necessary to decrease FPG/HbA1c to be under
the threshold values, a short/rapid-acting insulin may be added as
recue therapy starting with a single daily administration that
should be given at another meal than breakfast in the fixed ratio
combination group, and at any meal for the insulin glargine group.
No other OAD or basal insulin should be used as recue mediation in
any of the treatment arms. All assessments planned at the end of
treatment visit are to be performed before initiating recue
therapy. After these assessments are completed and recue therapy
initiated, the patient will remain in the study and continue to
administer the study treatment (including background therapy) The
planned visits and assessments (except the standardized meal test)
should be performed until the last scheduled visit. ENDPOINT(S)
Primary endpoint Change in HbA1c from baseline to week 30.
Secondary Endpoints(s) Efficacy: Percentage of patients reaching
HbA1c < 7% or .ltoreq. 6.5% at week 30 Change in 2-hour PPG and
in blood glucose excursion during standardized meal test from
baseline to week 30; Change in body weight from baseline to week
30; Change in 7-point SMPG profiles from baseline to week 30 (each
time point and average daily value); Percentage of patients
reaching HbA1c < 7% with no body weight gain at week 30; Change
in daily dose of insulin glargine from baseline to week 30; Change
in FPG from baseline to week 30; Percentage of patients reaching
HbA1c < 7% at week 30 with no documented [PG .ltoreq. 70 mg/dL
(3.9 mmol/L)] symptomatic hypoglycemia during the 30-week
randomized treatment period; Percentage of patients reaching HbA1c
< 7% with no body weight fain at week 30 and with no documented
[PG .ltoreq. 70 mg/dL (3.9 mmol/L)] symptomatic hypoglycemia during
the 30-week randomized treatment period; Change in 30-minute and
1-hour PPG and blood-glucose excursion during standardized meal
test from baseline to week 30; Percentage of patients requiring a
recue therapy during 30- week open-label treatment period. Safety:
Symptomatic hypoglycemia (documented, probably, severe symptomatic
hypoglycemia); Adverse events, serious adverse events and AESI,
safety laboratory values, vital signs, and Electrocardiogram (ECG);
Immunogenicity (antibody variables): Anti-lixisenatide antibodies
and/or anti-insulin antibodies (depending on the treatment group)
will be measured at Day 1 of the treatment phase and at Week 30.
Other Endpoints(s) Pharmacokinetics parameters Total and active
plasma concentrations of lixisenatide will be assessed in the time
frame from 1 to 4 hours post-injection at Day 1 of the treatment
phase and prior to injection as well as in the time frame from 1 to
4 hours post-injection at Week 30 (for patients in the insulin
glargine/lixisenatide fixed ratio combination). Patient Reported
Outcomes (PROs) Changes in patient reported outcomes (PRO) scores
will be assessed from baseline to week 30 for Treatment related
impact measure-diabetes (TRIM-D), EuroQol-5D (EQ-5D), and impact of
Weight on Quality of Life-Lite (IWQoL-Lite) questionnaires;
Patient- and physician-rated global treatment effectiveness
evaluation scale will also be evaluated at the end of the study.
ASSESSMENT Visit schedule: SCHEDULE The schedule of study-related
procedures/assessments is detailed in Study Flowchart (Section
1.2). Early termination: Patients who prematurely and permanently
discontinue IMP administration for any reason should have as soon
as possible a visit with assessments normally planned for the last
dosing day with the IMP, ie, "final on-treatment assessment",
including PK and antibody samples, mean test and PRO assessments,
if possible. Note: Patients who prematurely discontinued the IMP
should continue in the study up to the schedule state of study
completion. They should be followed up according to the study
procedures as specified in the protocol (Except 3-day safety
post-treatment follow- up, PK and antibody assessments, meal test
and PRO assessments). STATISTICAL Sample size determination
CONSIDERATIONS A sample size of 350 patients per arm will provide
more than 95% power to detect a difference of 0.4% in the HbA1c
change from baseline to week 30 between the insulin
glargine/lixisenatide fixed ratio combination and insulin glargine.
This calculation assumes a common standard deviation of 1.1% at the
5% significance level (2- sided). Analysis Population: The primary
efficacy population will be the modified Intent-To-Treat (mITT)
population, which includes all randomized patients who received at
least one dose of investigational medicinal product, and have both
a baseline assessment and at least one post-baseline assessment of
any primary or secondary efficacy endpoints, irrespective of
compliance with the study protocol and procedures. Patients will be
analyzed in efficacy analyses by the treatment regimen allocated by
the IVRS/IWRS according to the randomization schedule at
randomization visit (as randomized). The safety analysis will be
conducted on the safety population, defined as all randomized
patients exposed to at least one dose of investigational medicinal
product, regardless of the amount of treatment administered.
Patients will be analyzed according to the treatment regimen
actually received. Primary efficacy endpoint analysis Analyses of
the primary efficacy endpoint (change from baseline to week 30 in
HbA1c) will be performed using the mITT population, using HbA1c
values obtained from the scheduled visits during the on-treatment
period. The on-treatment period for HbA1c is defined as the time
from the first dose of investigational medicinal product to 14 days
after the last dose or up to the introduction of rescue therapy,
whichever is the earliest. The statistical test will be two- sided
at the alpha level of 0.05. The primary analysis method for the
primary efficacy endpoint will be a mixed-effect model with
repeated measures (MMRM) under the missing at random framework. The
MMRM model will include the treatment groups, randomization strata,
visit, treatment-by-visit interaction, and country as fixed-effect
factors, and the baseline HbA1c-by-visit interaction as covariate.
The baseline value is defined as the last available value prior to
the first dose administration of investigational medicinal product.
The adjusted mean change in HbA1c from baseline to Week 30 for each
treatment group will be estimated in the framework of this model,
as well as the between-group difference and the 95% CI for the
adjusted mean. The MMRM model will be run using SAS .RTM. (Version
9.2 or higher) MIXED procedure (PROC MIXED) with an unstructured
correlation matrix to model the within-patient errors. Parameters
will be estimated using the restricted maximum likelihood method
with the Newton-Raphson algorithm. Denominator degree of freedom
will be estimated using the Kenward-Roger approximation by fitting
values from post-randomization scheduled visits in the on-treatment
period. This model will use only scheduled HbA1c measurements
obtained during the on-treatment period. For the primary efficacy
endpoint, sensitivity analyses will be performed as necessary to
explore different methods for handling missing data. Secondary
efficacy endpoint analysis The continuous secondary efficacy
endpoints will be analyzed using a similar MMRM method. Differences
between treatment groups and confidence intervals will be estimated
within the framework of MMRM. Categorical efficacy endpoints will
be analyzed by Cochran- Mantel-Haenszel method stratified by the
randomization strata. Safety analysis Safety analyses for the
30-week treatment period will be descriptive, based on the safety
population (randomized and exposed). Treatment-emergent adverse
events (TEAEs) are defined as adverse events (AEs) that developed
or worsened or became serious during the period from the
administration of first dose of the study treatments up to 3 days
after the last administration. Pharmacokinetics parameters
Lixisenatide plasma concentrations (total and active) of patients
in the insulin glargine/lixisenatide fixed ratio combination group
will be listed and summarized by visit and time window and by anti-
lixisenatide antibody status in the PK population, using
descriptive statistics by N, geometric mean, coefficient of
variation, median, minimum and maximum. Patient Reported
Outcomes
Descriptive statistics (mean, median, standard deviation and range)
for absolute values and for changes from baseline (TRIM-D, EQ-5D
and IWQOl-Lite) will be presented by treatment arm per visit for
the global score, sub-scores as well as for each item of the three
PROs questionnaires. Descriptive statistics (mean, median, standard
deviation and range) for patient- and physician-rated global
evaluation scales will also be presented by treatment arm at the
end of the study. DURATION OF Maximum duration of approximately 39
weeks: an up to 8-week STUDY PERIOD (per screening period (with an
up to 2-week screening phase and a 6- patient) week run-in phase),
a 30-week randomized treatment period and 3 days post-treatment
safety follow up period.
1.2 Study Flow Chart
TABLE-US-00003 [0189] Study period Post- Screening period.sup.a
treatment Screening follow-up phase Run-in phase Open-label
randomization treatment period.sup.a visit VISIT: Time window:
V3-5: .+-.3 days/V 7-15: .+-.3 days/V 16-21: .+-.5 days/V 22: -1/+3
day 22 V21 + 3 4 7 9 11 12 14 16 18 20 3 days 1 2 5 6 8 10 13 15 17
19 21.sup.b WEEK -8 -6 -4 -2 -1 0 1 2 3 4 5 6 8 10 12 15 18 21 24
27 30 Informed Consent x Inclusion/Exclusion Criteria x x x
Medical, surgical, diabetes, x cardiovascular & allergy
history, alcohol & smoking habits, demography, prior
medications Physical Examination x x x Height x Body weight x x x x
x x x x Vital Signs x x x x x x x x x x x 12-lead ECG x x Diet and
Lifestyle counseling x x IVRS/IWRS contact x x x x x x x x x x
Randomization x Concomitant medication Continuously assessed and
recorded all along the study recording AE/SAE/Hypoglycemia
Glucometer dispensation & x training (including training on
glucose measurements).sup.c Diary dispensation/collection x x x x x
x x x x x (reviewed at each on-site visit) Training to
self-injection with x Lantus .RTM. Solostar .RTM..sup.c Insulin
glargine (Lantus .RTM. x x x x x x x Solostar .RTM.) dispensation
Training to injection using x disposable fixed ratio combination
pens (Pen A and Pen B).sup.c Fixed ratio combination pen x x x x x
x dispensed Daily fasting SMPG x x x x x x x x x x x x x x x x x x
x x 7-point SMPG profiles (on 2 x x x different days in the week
prior to the visit) Insulin glargine dose x x x x x x x x x x x x x
x x x x x x x adjustment Fixed ratio combination dose x x x x x x x
x x x x x x x adjustment Record of IMPs doses (on the x x x x x x x
x x x x x x x x x x x x last 3 days each week until week 12 and
then the last 3 days in the week before each visit).sup.d Count
returned pens x x x x x x x x Compliance check x x x x x x x x x x
x x x x x x x x x x PROs questionnaires (TRIM- x x x D, EQ-5D,
IWQoL-Lite) Patient-rated Global treatment x effectiveness Scale
Physician-rated Global x treatment effectiveness evaluation Scale
Central Laboratory testings HbA.sub.1c (central laboratory) x x x x
x x x Fasting Plasma Glucose x x x x x x x x (central laboratory)
2-h standardized meal test x x Total-; LDL-; HDL- x x Cholesterol,
triglycerides Urinalysis.sup.e & Hepatitis B x surface antigen
and hepatitis C antibody Albumin/creatinine ratio (1st x x morning
urines) Women only: FSH, Estradiol x (if necessary to define
menopausal status) Women only: serum x x x x pregnancy test (if
childbearing potential) Safety laboratory.sup.f: x x x x
hematology, serum chemistry Amylase, Lipase x x x x x x x x Serum
Calcitonin x x x x Anti-lixisenatide antibodies x x.sup.g and/or
anti-insulin antibodies (depending on the treatment group).sup.h
Lixisenatide total and active x x plasma concentration (fixed ratio
combination treatment group) Optional pharmacogenetic x
sampling.sup.i .sup.aAdditional phone calls for titration purposes
should be scheduled as often as deemed necessary by the
Investigator; Run-in visit (V2) can be performed less than 2 weeks
after screening visit (V1) if the laboratory data are available.
.sup.bIn case of rescue therapy, all assessments (including 2-hour
standardized meal test but except for PK and antibody assessments)
planned in V21 should be performed before starting rescue
medication, patients then continue the IMP treatment, and all visit
and assessments (including PK and antibody assessments but except
for meal test, and PRO assessments) should be performed as
scheduled. In case of premature IMP discontinuation, all
assessments (including 2-hour standardized meal test only if the
patient received the UMP the day of the meal test) planned in V21
should be performed before premature IMP discontinuation, patients
should continue in the study up to the scheduled date of study
completion, and all assessments (except the 3-day safety
post-treatment follow-up, meal test, PK and antibody assessments,
and PRO assessments) should be performed as schedule.
.sup.cRepeated as often as necessary. .sup.dMissed IMP injection
should be recorded in the e-CRF. .sup.eScreening urinalysis: (pH,
glucose, ketones, leucocytes, blood, protein). .sup.fSafety
Laboratory: hematology = WBC, RBC, Hemoglobin, Hematocrit,
platelets, differential blood count (Neutrophils, lymphocytes,
monocytes, eosinophils, basophils). Serum chemistry = total
bilirubin, G-GT, AST, ALT, ALP, creatinine, uric acid, sodium,
potassium, phosphorus, calcium. .sup.gOne additional sample will be
taken at Week 30 for potential additional measurements of
immunogenicity. .sup.hSamples for antibody assessment to be taken
prior to injection. .sup.iSamples could also be collected at any
later visit
List of Abbreviations
[0190] ADA American Diabetes Association [0191] AE Adverse event
[0192] AESI Adverse Event of Special Interest [0193] ALP Alkaline
phosphatase [0194] ALT Alanine aminotransferase [0195] ANCOVA
Analysis of covariance [0196] ARAC Allergic reaction assessment
committee [0197] AST Aspartate aminotransferase [0198] BID Bis in
die=twice daily [0199] BMI Body mass index [0200] bpm Beat per
minute [0201] CAC Cardiovascular events Adjudication Committee
[0202] CRF Case report form [0203] CSR Clinical study report [0204]
CI Confidence Interval [0205] CMH Cochran-Mantel-Haenszel [0206]
CMPC Committee for Proprietary Medicinal Products [0207] CT
Computerized tomography [0208] D Day [0209] DBP Diastolic blood
pressure [0210] dL Deciliter [0211] DNA Deoxyribonucleic acid
[0212] DMC Data Monitoring Committee [0213] DRF Discrepancy
resolution form [0214] eg Exempli gratia=for example [0215] EASD
European association for the study of diabetes [0216] ECG
Electrocardiogram [0217] e-CRF Electronic case report form [0218]
EQ-5D EuroQol five dimension [0219] EDTA Ethylene diamine
tetra-acetic acid [0220] ELISA Enzyme linked immuno-sorbent assay
[0221] FPG Fasting plasma glucose [0222] FSH Follicle stimulating
hormone [0223] FU Follow up [0224] GCP Good Clinical Practice
[0225] G-GT Garnma-glutamyl transpeptidase [0226] GI
Gastro-Intestinal [0227] GLP-1 Glucagon like peptide-1 [0228] GSO
Global Safety Officer [0229] HbA1c Glycated hemoglobin Ale [0230]
HBsAg Hepatitis B surface antigen [0231] HCAb Hepatitis C antibody
[0232] HDL High density lipoprotein [0233] HLGT High Level Group
Term [0234] HLT High Level Term [0235] HRQoL Health related quality
of life [0236] ICH International Conference on Harmonization [0237]
1e Id est=that is [0238] IEC Independent ethics committee [0239]
IMP Investigational medicinal product [0240] IND Investigational
new drug [0241] INR International normalized ratio [0242] IRB
Institutional review board [0243] ITT Intention-to-treat [0244]
IVRSIIWRS Interactive voice/web response system [0245] IWQOL-lite
Impact of weight on quality of life [0246] kg Kilogram [0247] LDL
Low density lipoprotein [0248] LOCF Last observation carried
forward [0249] LLOQ Lower Limit of Quantification [0250] LLT Lower
Level Term [0251] MTC Medullary thyroid cancer [0252] MedDRA
Medical Dictionary for Drug Regulatory Affairs [0253] Met Metformin
[0254] MMRM Mixed-effect model with repeated measures [0255] MRI
Magnetic resonance imaging [0256] .mu.g Microgram [0257] mITT
Modified intention-to-treat [0258] mL Milliliter [0259] mmHg
Millimeters of mercury [0260] mmol Millimole [0261] ms Millisecond
[0262] N Number [0263] NGSP National glycohemoglobin
standardization program [0264] OAD Oral anti-diabetic [0265] oc
Observed cases [0266] PCSA Potentially clinically significant
abnormalities [0267] pg Picogramme [0268] PK Pharmacokinetic [0269]
pmol Picomole [0270] PPG Postprandial plasma glucose [0271] PRO
Patient report outcome [0272] PSAC Pancreatic safety assessment
committee [0273] PT Preferred term [0274] PIC Product technical
complaint [0275] QD Quague die=once daily [0276] QoL Quality of
life [0277] RBC Red blood cell count [0278] s Second [0279] S.C.
Subcutaneous [0280] SAE Serious adverse event [0281] SAS
Statistical Analysis System [0282] SBP Systolic blood pressure
[0283] SD Standard deviation [0284] SM PG Self-measured plasma
glucose [0285] soc System organ class [0286] su Sulfonylurea [0287]
T2DM Type 2 diabetes mellitus [0288] TEAE Treatment emergent
adverse event [0289] TRIM-D Treatment-related impact measure for
diabetes [0290] TSH Thyroid Stimulating Hormone [0291] ULN Upper
limit of normal range [0292] v Visit [0293] VAS Visual analogue
scale [0294] WBC White blood cell count [0295] WHO World health
organization [0296] WHO-DD World health organization-Drug
Dictionary
3 INTRODUCTION AND RATIONALE
[0297] The present Example will evaluate the efficacy and safety of
the combination of basal insulin glargine (Lantus.RTM.) and the
GLP-1 receptor agonist lixisenatide in patients with T2DM not
sufficiently controlled on basal insulin.
[0298] Lixisenatide (AVEOO10) is a polypeptide with pronounced
GLP-1 agonistic activities which has been approved in 2013 in the
European Union, Japan, Mexico, and Australia (under tradename
Lyxumia.RTM.) and has been filed in several other countries. The
current approved indication of Lyxumia.RTM. in EU is the treatment
of adults with type 2 diabetes mellitus to achieve glycaemic
control in combination with oral glucose-lowering medicinal
products and/or basal insulin when these, together with diet and
exercise, do not provide adequate glycaemic control.
[0299] Insulin glargine (HOE901 or Lantus.RTM.) an analogue of
human insulin provides 24-hour basal insulin supply after single
dose subcutaneous injection. Lantus.RTM. has been marketed since
June 2000 in Europe and since May 2001 in the USA and other parts
of the world. Lantus.RTM. is indicated for the treatment of adult
and pediatric patients with TIDM or adult patients with T2DM who
require basal (longacting) insulin for the control of
hyperglycemia.
[0300] Since both lixisenatide and insulin glargine are efficacious
when given once daily, and have similar physicochemical features
such as good solubility at low pH, both components can be mixed as
a defined fixed ratio formulation to be delivered by one single
injection.
[0301] Type 2 Diabetes Mellitus (T2DM) is characterized by a
gradual deterioration of glucose control. Even with multiple oral
antidiabetic drugs (OADs), a substantial proportion of patients
eventually needs the addition of insulin therapy to achieve and
maintain glycated hemoglobin (HbA1c) targets. The transition from
OADs to insulin is generally conducted by adding basal insulin to
existing OADs and usually is an efficient step in controlling
fasting plasma glucose (FPG) levels, when the beta cell still has
enough function to cover meals with intrinsic insulin synthesis or
secretion. Approximately 60% of T2DM patients treated with basal
insulin do not reach HbA1c target of <7%. Further increasing the
dose of basal insulin or adding other agents that also target FPG
is often associated with weight gain and hypoglycemic events. These
and other factors result in poor persistence and adherence to
treatment in a sizable proportion of patients.
[0302] The combination of basal insulin with a GLP-1 receptor
agonist (GLP-1 RA) might offer a significant advantage over
existing modality of treatment intensification for patients not
able to achieve good glycemic control with basal insulin. In
addition to improving glycemic control in patients already being
treated with basal insulin, the association of the two can maximize
other
[0303] benefits and at the same time minimize some of the
limitations of each one. While the studies conducted to date are
heterogeneous in their design, generally speaking, the combination
promises to increase the number of patients at target with minimal
weight gain or even weight loss while maintaining a manageable
hypoglycemia profile. Therefore the combination of basal insulin
with a GLP-1 receptor agonist may provide an improvement of the
benefit/risk when compared to each one used individually.
[0304] As basal insulin products target primarily, although not
exclusively, fasting hyperglycemia, and are often given once daily,
the most desirable combination would be with a GLP-IRA such as
lixisenatide, which, when given once daily, still effectively acts
on post-prandial glycemia due to slowing down gastric emptying even
when the ability to restore glucose sensitive insulin secretion is
exhausted or limited.
[0305] There is still an unmet need in patients with uncontrolled
type 2 diabetes despite basal insulin. A very significant
proportion of patients were able to achieve FPG goals but not HbA1c
goals. A therapeutic strategy targeting both FPG and PPG components
of HbA1c could help to address this unmet medical need. The present
Example intends to demonstrate this for the combination of insulin
glargine and lixisenatide.
[0306] The lixisenatide standalone product has been developed and
approved in the EU at a fixed dose of 20 .mu.g QD. The dosing of
lixisenatide in the combination will be variable and range from 5
to 20 .mu.g QD.
[0307] In this combination insulin glargine and lixisenatide will
be mixed in two fixed ratios solutions delivered by prefilled
disposable pen injectors. The dose of the combination will be
titrated depending on the insulin needs of the patient, from 10 U
insulin glargine/5 .mu.g lixisenatide to 60 U insulin glargine/20
.mu.g lixisenatide. The 2 fixed ratios of the components are
proposed to obtain a good pharmacological effect within established
tolerability limits. The lower end of the dosing range of
lixisenatide is defined by the minimum dose for efficacy, the upper
end by available safety database. Data derived from studies in T2DM
patients and healthy subjects demonstrate that doses of 5-10 .mu.g
lixisenatide could provide sufficient concentrations to stimulate
glucose-sensitive insulin release and have demonstrated efficacy on
HbA1c, while doses of 10 .mu.g have also demonstrated a potent
effect on inhibition of gastric emptying.
[0308] Based on the above considerations, the following two pens
with 2 different strengths of the combination will be used in the
present Example: Pen A will deliver a dose from 10 U insulin
glargine/5 .mu.g lixisenatide to 40 U insulin glargine/20 .mu.g
lixisenatide [2 (units) to 1(.mu.g) ratio], while pen B will
deliver a dose from 30 U insulin glargine/10 .mu.g lixisenatide to
60 U insulin glargine/20 .mu.g lixisenatide [3 (units) to 1(.mu.g)
ratio].
[0309] The dose of the combination will be titrated depending on
the insulin glargine needs of the patient. Only the insulin
glargine dose appears in the pen dosing window. The dose (.mu.g) of
lixisenatide does not appear in the dose window although
lixisenatide is pre-mixed in the cartridge. The lixisenatide dose
is increased or decreased concomitantly with any insulin glargine
dose change and also depends on the insulin glargine/lixisenatide
fixed ratio of the combination product. Pen A is intended to be
used for patients requiring insulin glargine doses between 10 and
40 U, Pen B is intended to be used for patients requiring insulin
glargine doses between 40 and 60 U. It may also be used for insulin
glargine doses between 30 and 40 U either at initiation of
treatment or during the treatment phase to allow temporary 5 days)
dose decrease e.g. in case of hypoglycemia without necessitating a
return to pen A.
[0310] The primary objective of the current Example is to
demonstrate over 30 weeks the superiority on HbA1c reduction of the
insulin glargine/lixisenatide combination to insulin glargine
(.+-.metformin for both treatments) in patients not sufficiently
controlled on basal insulin.+-.oral anti-diabetic treatments.
[0311] The secondary objectives are to assess the effects of the
insulin glargine/lixisenatide combination versus insulin glargine
on percentage of patients reaching HbA1c targets, glycemic control
during a standardized meal test, body weight, composite endpoints
of percentage of patients reaching HbA1c target (<7%) with no
weight gain and/or documented symptomatic hypoglycemia, 7-point
Self-Monitored Plasma Glucose (SMPG) profile, insulin glargine dose
and fasting Plasma Glucose. Other endpoints include health related
quality of life.
[0312] These endpoints focusing not only on glucose-lowering
effects and HbA1c but also on other parameters such as weight and
hypoglycemia are considered appropriate to demonstrate the expected
benefits from the insulin glargine/lixisenatide fixed ratio
combination.
[0313] Screened patients who satisfy all entry criteria, will enter
a 6-week run-in phase for introduction and/or adjustment of insulin
glargine doses (individually adapted according to investigators
judgment based on the results of the fasting SMPG levels).
Anti-diabetic treatment other than metformin will be stopped at
entry in the run-in phase. Metformin treatment if previously taken
will be continued.
[0314] At the end of this run-in phase, patients with
HbA1c.gtoreq.7% and 0%, a mean fasting SMPG calculated from the
self-measurements for the 7 days prior to randomization
visit.ltoreq.140 mg/dL (7.8 mmol/L) and a daily insulin glargine
dose.gtoreq.20 U or .ltoreq.50 U, will enter a 30-week open-label
randomized treatment period comparing the fixed ratio combination
to insulin glargine. This treatment period duration is considered
sufficient to allow an appropriate evaluation of the effect on
HbA1c, plasma glucose levels, body weight and other secondary
endpoints.
[0315] Patients having at randomization a daily insulin glargine
dose<30 U will start the combination treatment with Pen A at a
dose of 20 U of insulin glargine/10 .mu.g of lixisenatide, those
receiving 30 U or more will start the combination treatment with
pen B at a dose of 30 U of insulin glargine/10 .mu.g of
lixisenatide. After a transition phase during the first 4 week(s)
of treatment (see Section 7.2.4), doses will be titrated once a
week to achieve glycemic targets [fasting self-monitored plasma
glucose (SMPG) in the range of 80 to 100 mg/dL (4.4 to 5.6 mmol/L)]
without hypoglycemia. In order not to go above a 20 .mu.g daily
dose of lixisenatide, the maximal daily dose of insulin glargine
that can be administered in the fixed ratio combination treatment
arm is 60 U. Therefore the maximal dose of insulin glargine allowed
in the insulin glargine alone arm will also be 60 U/day in order to
best investigate the additional impact of the lixisenatide
component of the insulin glargine/lixisenatide fixed ratio
combination on glucose control.
[0316] Both treatments should be administered once daily by deep
subcutaneous injection. The insulin glargine/lixisenatide fixed
ratio combination is to be injected within one hour prior to
breakfast. Insulin glargine can be injected at any time of the day
(but approximately at the same time every day). The injection time
will be determined at Visit 2. This time injection should remain
the same throughout the study (during run-in phase for all patients
and also during the randomized treatment period for patients
randomized to the insulin glargine treatment group). Patients
randomized to the fixed ratio combination group and who previously
received insulin glargine at another time of the day than morning
will have to switch to an administration within one hour prior to
breakfast. A procedure for transitioning time administration is
proposed in Section 7.2.4.
[0317] Potential safety signals for acute pancreatitis had been
identified in the post-marketing experience of other GLP-1 receptor
agonists. Therefore, patients enrolled in this study should be
followed for any suspected pancreatitis, e.g. with symptoms and/or
signs of acute abdominal distress or abnormal levels of pancreatic
enzymes. Serum amylase and lipase concentrations are monitored
routinely at screening, baseline and periodically during the study
treatment period. As this monitoring may be difficult in patients
who already have high values of amylase or lipase, patients with
values above 3 times the upper limit of normal range at screening
will not be included in the study. Guidance for Investigators on
the follow-up of suspected pancreatitis is specified in the
protocol. In addition, selected pancreatic events, including
pancreatitis, pancreatic neoplasms and abnormal levels of amylase
or lipase, will be reviewed by a panel of blinded, external experts
(Pancreatic Safety Assessment Committee).
[0318] Information from Victoza.RTM. pre-clinical carcinogenicity
studies has raised the issue of a potential increased risk of
thyroid C-cell hyperplasia and neoplasm. Following a request of the
health authorities concerning any clinical study longer than 3
months with a GLP-1 receptor agonist, serum calcitonin will be
monitored in the present Example as a marker of thyroid C-cell
hyperplasia and neoplasm, with specific monitoring implemented for
patients with value.gtoreq.20 .mu.g/mL (5.9 pmol/L). As this
monitoring may be difficult in patients who already have high
values, those with calcitonin values equal to or above 20 .mu.g/mL
(5.9 pmol/L) at screening will not be included in the study.
Conclusion on the Benefit Risk Assessment in this Study:
[0319] The insulin glargine/lixisenatide fixed ratio combination is
the combination of two products with demonstrated glucose-lowering
properties and which are approved in Europe for the treatment of
adult patients with T2DM to improve glycemic control.
[0320] The type and incidence of adverse events observed in
previous lixisenatide clinical studies covering daily doses of up
to 60 .mu.g, and in the insulin glargine/lixisenatide fixed ratio
combination Phase 2 Study of Example 1 with daily doses up to 60 U
of insulin glargine/30 .mu.g of lixisenatide did not reveal
findings or concerns precluding the continuation of clinical
development. Given the safety profile observed in the completed
studies, combined treatment of insulin glargine and lixisenatide in
a fixed ratio solution can be considered well tolerated and no
particular risk has been identified for the population to be
included in the present Example. Therefore, the risk profile for
patients participating in this study, using daily doses up to 60 U
of insulin glargine/20 .mu.g of lixisenatide is considered
limited.
[0321] All patients entering this study will receive treatment with
insulin glargine/lixisenatide fixed ratio combination or insulin
glargine, which should improve their glycemic control. In addition,
all patients will benefit from close management of their T2DM.
[0322] Rescue therapy is planned and described in the clinical
study protocol for patients whose glycemia is poorly
controlled.
[0323] Given the expected improvement of metabolic control and the
additional measures to improve diabetes management, these benefits
are considered to outweigh the limited risk associated with the
insulin glargine/lixisenatide fixed ratio combination drug.
Therefore the benefit-risk ratio for patients participating in the
present Example is considered favorable.
4 STUDY OBJECTIVES
4.1 Primary
[0324] The primary objective of this study is to demonstrate over
30 weeks the superiority on HbA1c reduction of the insulin
glargine/lixisenatide fixed ratio combination versus insulin
glargine in type 2 diabetic patients with or without metformin.
4.2 Secondary
[0325] The secondary objectives of this study are [0326] To assess
over 30 weeks the effects of the insulin glargine/lixisenatide
fixed ratio combination versus insulin glargine on: [0327]
Percentage of patients reaching HbA1c targets; [0328] Glycemic
control in relation to a meal as evaluated by glucose excursion and
2-hour Post-prandial Plasma Glucose (PPG) during a standardized
meal test; [0329] Body weight; [0330] 7-point Self-Monitored Plasma
Glucose (SMPG) profile; [0331] Percentage of patients reaching
HbA1c targets with no body weight gain and/or documented
symptomatic hypoglycemia; [0332] Insulin glargine dose; [0333]
Fasting Plasma Glucose (FPG). [0334] To assess the safety and
tolerability in each treatment group; [0335] To assess the
development of anti-insulin antibodies and anti-lixisenatide
antibodies (fixed ratio combination treatment group for the
latter); [0336] To assess the total and active plasma concentration
of lixisenatide before and following injection (fixed ratio
combination treatment group); [0337] To assess the treatment
effects of each treatment group on Patient Reported Outcomes (PROs)
measured by the following questionnaires: [0338] Treatment related
impact measure-diabetes (TRIM-D), [0339] EuroQol-5D (EQ-5D), [0340]
Impact of Weight on Quality of Life-Lite (IWQoL-Lite). [0341] To
assess patients overall response to treatment for each treatment
group using patient- and physician-rated global treatment
effectiveness evaluation scales.
5 STUDY DESIGN
5.1 Description of the Protocol
[0342] This is an open-label, 1:1 randomized, active-controlled,
2-arm, 30-week treatment duration, parallel-group multinational and
multicenter phase III study.
[0343] The study will recruit outpatients with T2DM. At baseline
visit, the patient will be randomized to either one of the
following two treatment groups: [0344] Insulin
glargine/lixisenatide fixed ratio combination group [0345] Insulin
glargine group
[0346] The patients will be stratified by value of HbA1c at visit 5
(week -1) (<8%, .gtoreq.8%) and metformin use at screening (Y,
N).
[0347] The study will comprise 3 periods: [0348] An up-to 8-week
screening period, which includes [0349] An up to 2-week screening
phase: Run-in visit can be performed less than 2 weeks after
screening visit if the laboratory data are available. [0350] A
6-week run-in phase: Switching to (if appropriate) and/or dose
optimization of insulin glargine, continuing metformin (if
appropriate) and stopping sulfonylurea, glinide, SGLT-2 inhibitor
or DPP-4 inhibitor if previously taken at V2. [0351] A 30-week
open-label randomized treatment period [0352] At the end of the
screening period, patients whose HbA1c is .gtoreq.7% and
.ltoreq.10%, whose mean fasting Self Monitored Plasma Glucose
(SMPG) calculated from the self-measurements for the 7 days prior
to randomization visit is 140 mg/dL (7.8 mmol/L) and whose insulin
glargine daily dose is .gtoreq.20 U or .ltoreq.50 U, will enter a
30-week, open-label randomized treatment period comparing
lixisenatide/insulin glargine fixed ratio combination to insulin
glargine (.+-.metformin for both treatments).
[0353] A 3-day post-treatment safety follow-up period for all the
patients after permanent IMP discontinuation (except for patients
who prematurely discontinue the study treatment; those patients
should continue in the study up to the scheduled date of study
completion)
5.2 Duration of Study Participation
5.2.1 Duration of Study Participation for Each Patient
[0354] The maximum study duration per patient will be approximately
39 weeks: an up to 8-week screening period (with an up to 2-week
screening phase and a 6-week run-in phase), a 30-week randomized
treatment period and 3 days post-treatment safety follow up
period.
5.2.2 Determination of End of Clinical Trial (all Patients)
[0355] The end of the study is defined as being the "last patient
last visit" planned with the protocol, including follow-up
visit.
5.3 Interim Analysis
[0356] Please refer to Section 10.5.
5.4 Study Committees
5.4.1 Data Monitoring Committee
[0357] A Data Monitoring Committee (DMC) with members who are
independent from the sponsor and the investigators will be used to
make appropriate recommendations on the conduct of the clinical
trial for ensuring the protection and the safety of the enrolled
patients in the study. The DMC reviews and analyzes, on a regular
basis, unblinded safety data provided by an independent statistical
group throughout the study, as well as safety data from the other
ongoing clinical studies conducted with lixisenatide (except the
cardiovascular study). A detailed charter outlines the activities
of the DMC.
5.4.2 Allergic Reaction Assessment Committee
[0358] Since lixisenatide is a peptide that may potentially
generate allergic reactions an Allergic Reaction Assessment
Committee (ARAC) has been set up. The ARAC is a committee of
experts in the field of allergy, independent from the Sponsor and
the Investigators, implemented to assess allergic reactions or
allergic-like reactions that may occur during the study. The
mission of the ARAC will be to adjudicate, in a timely manner, all
allergic, or possible allergic events. The ARAC will review the
cases in a blinded manner with regard to study treatment.
[0359] The ARAC will review the reported cases, determine the
nature of the events, and confirm the allergic nature or
alternative diagnosis based on the information reported by the
Investigator. A detailed charter describes the ARAC procedures.
5.4.3 Cardiovascular Events Adjudication Committee
[0360] Following regulatory agency requirements to better assess
the impact of newly developed diabetes treatments on cardiovascular
events and to adjudicate significant cardiovascular events, an
independent Cardiovascular events Adjudication Committee (CAC) has
been set up. The CAC is a committee of experts in the field of
cardiovascular or cerebrovascular diseases, independent from the
Sponsor and the Investigators, implemented to adjudicate major
cardiovascular events that may occur during the study. The CAC will
review the cases in a blinded manner with regard to study
treatment, at the latest before the database lock. A detailed
Manual of Operations describes the CAC procedures.
5.4.4 Pancreatic Safety Assessment Committee
[0361] Potential safety signals for acute pancreatitis had been
identified in the post-marketing experience of other GLP-1 receptor
agonists. Specific monitoring for pancreatic events is planned in
this study (see Section 9.6.4) and a Pancreatic Safety Assessment
Committee (PSAC) has been set up. This is a committee of experts in
the field of pancreatitis and pancreatic neoplasm, independent from
the Sponsor and the Investigators, implemented to assess pancreatic
events that may occur during the study. The PSAC will review
selected pancreatic events, including pancreatitis, pancreatic
neoplasms and abnormal levels of amylase or lipase. This review
will be conducted in a blinded manner with regard to study
treatment. A detailed charter describes the PSAC procedures.
6 SELECTION OF PATIENTS
6.1 Inclusion Criteria
[0362] Patients meeting all of the following inclusion criteria
will be screened: [0363] I 01. Patients with type 2 diabetes
mellitus diagnosed at least 1 year before the screening visit.
[0364] I 02. Patients who have been treated with basal insulin for
at least 6 months before the screening visit. [0365] I 03. Patients
who have been treated for at least 3 months prior to the screening
visit with a stable basal insulin regimen (i.e. type of insulin and
time/frequency of the injection). [0366] I 04. The total daily
basal insulin dose should be stable (.+-.20%) and between 15 and 40
U/day for at least 2 months prior to the screening visit. [0367] I
05. Patients who have been treated with basal insulin alone or in
combination with a stable dose for at least 3 months before the
screening visit of 1 to 2 OADs that can be: metformin (1500 mg/day
or maximal tolerated dose), a sulfonylurea (SU), a glinide, a
dipeptidyl-peptidase-4 (DPP-4) inhibitor or a SGLT-2 inhibitors.
[0368] I 06. Patients with FPG 180 mg/dL (10.0 mmol/L) at screening
visit. [0369] I 07. Signed written informed consent.
6.2 Exclusion Criteria
[0370] Patients who have met all the above inclusion criteria
listed in Section 6.1 will be screened for the following exclusion
criteria which are sorted and numbered in the following
subsections:
6.2.1 Exclusion Criteria Related to Study Methodology
[0371] E 01. At screening visit, age under legal age of adulthood.
[0372] E 02. At screening visit, HbA1c: <7.5% and >10.0%.
[0373] E 03. At screening visit, Body Mass Index (BMI).ltoreq.20 or
>40 kg/m.sup.2 [0374] E 04. History of hypoglycemia unawareness.
[0375] E 05. History of metabolic acidosis, including diabetic
ketoacidosis within 1 year prior to screening visit. [0376] E 06.
Use of other oral or injectable glucose-lowering agents than stated
in the inclusion criteria in a period of 3 months prior to
screening. [0377] E 07. Previous use of insulin regimen other than
basal insulin (e.g. prandial or pre-mixed insulin) more than 3
months ago. [0378] Note: Short term treatment due to intercurrent
illness including gestational diabetes is allowed at the discretion
of the investigator [0379] E 08. Previous use of insulin regimen
other than basal insulin (e.g. prandial or pre-mixed insulin) more
than 3 months ago. [0380] Note: Short term treatment due to
intercurrent illness including gestational diabetes is allowed at
the discretion of the investigator [0381] E 09. Discontinuation of
a previous treatment with GLP-1 RAs due to safety/tolerability
issue or lack of efficacy. [0382] E 10. Use of systemic
glucocorticoids (excluding topical and inhaled forms) for a total
duration of 1 week or more within 3 months prior to screening
visit. [0383] E 11. Use of weight loss drugs within 3 months prior
to screening visit. [0384] E 12. Use of any investigational drug
within 1 month or 5 half-lives, whichever is longer, prior to
screening visit. [0385] E 13. Patient who has previously
participated in any clinical trial with lixisenatide or the insulin
glargine/lixisenatide fixed ratio combination or has previously
received lixisenatide. [0386] E 14. Within the last 6 months prior
to screening visit: history of stroke, myocardial infarction,
unstable angina, or heart failure requiring hospitalization. [0387]
E 15. Planned coronary, carotid or peripheral artery
revascularisation procedures to be performed during the study
period. [0388] E 16. Known history of drug or alcohol abuse within
6 months prior to the time of screening visit. [0389] E 17.
Uncontrolled or inadequately controlled hypertension (systolic
blood pressure>180 mmHg or diastolic blood pressure>95 mmHg)
at screening visit. [0390] E 18. Conditions/situations such as:
[0391] Patients with conditions/concomitant diseases making them
non evaluable for the primary efficacy endpoint (e.g.,
hemoglobinopathy or hemolytic anemia, receipt of blood or plasma
products within the last 3 months prior to the screening visit)
[0392] Patients with conditions/concomitant diseases precluding
their safe participation in this study (e.g. active malignant
tumor, major systemic diseases, presence of clinically significant
diabetic retinopathy or presence of macular edema likely to require
treatment within the study period, etc.); Impossibility to meet
specific protocol requirements (e.g., scheduled visits, patients
unable to fully understand patient's study documents and to
complete them, etc.); [0393] Uncooperative or any condition that
could make the patient potentially non-compliant to the study
procedures (e.g. patient unable or unwilling to do self-injections
or blood glucose monitoring using the sponsor-provided blood
glucose meter at home, etc.); [0394] Patient is the Investigator or
any Sub-Investigator, research assistant, pharmacist, study
coordinator, other staff or relative thereof directly involved in
the conduct of the protocol. [0395] E 19. Laboratory findings at
the screening visit: [0396] Amylase and/or lipase: >3 times the
upper limit of the normal (ULN) laboratory range, ALT or AST: >3
ULN, [0397] Total bilirubin>1.5 ULN (except in case of Gilbert's
syndrome), Calcitonin 20 .mu.g/mL (5.9 pmol/L), [0398]
Hemoglobin<10.5 g/dL or neutrophils<1,500/mm.sup.3 or
platelets<100,000/mm.sup.3, [0399] Positive test for Hepatitis B
surface antigen and/or Hepatitis C antibody, Positive serum
pregnancy test. [0400] E 20. Any technical/administrative reason
that makes it impossible to randomize the patient in the study.
[0401] E 21. Patient who withdraws consent during the screening
period (screening phase and run-in phase). [0402] E 22. The target
number of randomized patients is reached.
6.2.2 Exclusion Criteria Related to the Active Comparator and/or
Background Therapy
[0402] [0403] E 23. Any contraindication to metformin use,
according to local labeling. (e.g. renal impairment defined as
creatinine>1.4 mg/dL in women, >1.5 mg/dL in men, or
creatinine clearance<60 mL/min, etc.) if the patient is taking
metformin. [0404] E 24. Contraindication to use of insulin glargine
according to local labeling. History of hypersensitivity to insulin
glargine or to any of the excipients.
6.2.3 Exclusion Criteria Related to the Tested IMP (Insulin
Glargine/Lixisenatide Fixed Ratio Combination)
[0404] [0405] E 25. Pregnancy or lactation. [0406] E 26. Women of
childbearing potential not protected by highly effective
contraceptive method of birth control (as defined for contraception
in the Informed Consent Form and/or in a local protocol addendum)
and/or who are unwilling or unable to be tested for pregnancy.
[0407] "Woman of childbearing potential not protected by
highly-effective method(s) of birth control (as defined for
contraception in the Informed Consent Form and/or in a local
protocol amendment in case of specific local requirement) and/or
who are unwilling or unable to be tested for pregnancy."-whether to
be changed is under confirmation. [0408] E 27. Clinically relevant
history of gastrointestinal disease associated with prolonged
nausea and vomiting, including (but not limited to): gastroparesis,
unstable (ie, worsening) or not controlled (i.e., prolonged nausea
and vomiting) gastroesophageal reflux disease requiring medical
treatment, within 6 months prior to the time of screening visit.
[0409] E 28. History of pancreatitis (unless pancreatitis was
related to gallstones and cholecystectomy was already performed),
chronic pancreatitis, pancreatitis during a previous treatment with
incretin therapies, pancreatectomy, stomach/gastric surgery. [0410]
E 29. Personal or immediate family history of medullary thyroid
cancer (MTC) or genetic conditions that predispose to MTC (eg,
multiple endocrine neoplasia syndromes). [0411] E 30. Patient who
has a renal function impairment with creatinine clearance<30
mL/min (using the Cockroft and Gault formula) or end-stage renal
disease for patients not treated with metformin. [0412] E 31.
Contraindication to use of lixisenatide (according to local
labeling if appropriate). History of allergic reaction to any GLP-1
receptor agonists including lixisenatide in the past or to
metacresol.
6.2.4 Additional Exclusion Criteria at the End of Screening Period
Before Randomization
[0412] [0413] E 32. Use of sulfonylurea, glinide, SGLT-2 inhibitor,
and DPP-4 inhibitor after start of run-in (from visit 2). [0414] E
33. HbA1c<7% or >10% at visit 5 (week -1). [0415] E 34. Mean
fasting SMPG calculated from the self-measurements for 7 days the
week before randomization visit (V6) is >140 mg/dL (7.8 mmol/L).
[0416] E 35. Average insulin glargine daily dose<20 U or >50
U calculated for the last 3 days the week before visit 6. [0417] E
36. Amylase and/or lipase>3 ULN at visit 5 (week -1). [0418] E
37. Patient with any AE, which, by the judgment of the Investigator
would preclude the inclusion in the open-label randomized treatment
period.
[0419] A patient should not enter the run-in phase or be randomized
more than once. In cases where original screen failure was due to
reasons expected to change at rescreening and based upon the
Investigator's clinical judgment, the patient can be rescreened one
time for this study.
7 STUDY TREATMENTS
7.1 Diet and Exercise
[0420] Lifestyle and diet therapy provided before the time of
screening is to be continued during the study in a similar manner.
Dietary and lifestyle counseling will be given by a healthcare
professional at visit 2 and visit 6, which should be consistent
with the recommendations of international or local guidelines (with
regard to the distribution of calories among carbohydrates,
proteins, and fats, exercise, etc.) for type 2 diabetic
patients.
[0421] Compliance with the diet and lifestyle counseling will be
assessed in case of insufficient glucose control (please refer to
Section 7.4).
7.2 Investigational Medicinal Product(S)
[0422] Insulin glargine/lixisenatide fixed ratio combination and
insulin glargine are considered as investigational medicinal
products (IMPs).
7.2.1 Formulations
[0423] Insulin glargine/lixisenatide fixed ratio combination
[0424] Insulin glargine/lixisenatide fixed ratio combination is
supplied as a sterile aqueous solution for subcutaneous (s.c.)
injection in a pre-filled disposable SoloStar.RTM. pen-injector
(100 U/mL insulin glargine with 50 .mu.g/mL or 33 .mu.g/mL
lixisenatide depending on the pen (pen A or B respectively).
[0425] Insulin Glargine
[0426] Insulin glargine is supplied as a sterile aqueous solution
for subcutaneous (s.c.) injection in a pre-filled disposable
SoloStar.RTM. pen-injector (100 U/mL insulin glargine).
7.2.2 Injection Devices and Training for Injection Devices
7.2.2.1 Injection Devices
[0427] Insulin glargine/lixisenatide fixed ratio combination (Pen A
or Pen B)
[0428] The combination product will be self-administered with a
pre-filled disposable SoloStar.RTM. pen-injector.
[0429] The dose of the combination is titrated according to the
patient's needs for insulin glargine. Note that only the dose of
insulin glargine appears in the pen dosing window. The dose (.mu.g)
of lixisenatide does not appear in the dose window although
lixisenatide is pre-mixed in the cartridge.
[0430] Two pens (A and B) with different insulin
glargine/lixisenatide fixed ratios are available to allow insulin
glargine titration over a range of 10 to 60 U/day while limiting
the lixisenatide dose to a maximum of 20 .mu.g/day: [0431] Pen A
(yellow label, yellow dose button): pre-filled disposable
SoloStar.RTM. pen-injector containing 3 mL of a sterile solution of
100 U/mL insulin glargine and 50 .mu.g/mL lixisenatide in ratio of
2:1 (2 units of insulin glargine per 1 .mu.g lixisenatide). Each
pen is specifically labeled for use in the study and contains in
total 300 units insulin glargine and 150 .mu.g lixisenatide in 3
ml. Printing on the number sleeve shows priming feature and doses
from 10 to 40 U which is the intended dose range for pen A (Please
see FIG. 16). [0432] Doses can be set from 10 to 40 units in steps
of 1 unit. Pen A allows administration of daily combination doses
between 10 U/5 .mu.g and 40 U/20 .mu.g. [0433] It would be
theoretically possible to dial more than 40 U or less than 10 U
insulin glargine (no mechanical upper or lower cap), but the dose
is not marked on the pen outside the intended range of 10 to 40 U.
[0434] Pen B (red label, red dose button): pre-filled disposable
SoloStar.RTM. pen-injector containing 3 mL of a sterile solution of
100 U/mL insulin glargine and 33 11 g/mL lixisenatide in ratio of
3:1 (3 units of insulin glargine per 1 11 g lixisenatide). Each pen
is specifically labeled for use in the study and contains in total
300 units insulin glargine and 99 .mu.g lixisenatide in 3 ml.
Printing on the number sleeve shows priming feature and doses from
30 to 60 U. (Please see FIG. 16). [0435] Doses can be set from 30
to 60 units in steps of 1 unit. Pen B allows administration of
daily combination doses between 30 U/10 .mu.g and 60 U/20 .mu.g.
[0436] It would be theoretically possible to dial more than 60 U or
less than 30 U insulin glargine (no mechanical upper or lower cap),
but the dose is not marked on the pen outside the intended range of
30 to 60 U. [0437] Pen B is intended mainly for use by patients
requiring daily insulin glargine doses between 40 and 60 U.
However, it may also be used for patients needing daily insulin
glargine doses between 30 and 40 U either at initiation of
treatment (see Section 7.2.4) or during the treatment phase to
allow a temporary (5 or 7 days?) dose decrease in dos e.g. in case
of hypoglycemia without the inconvenience of a change to pen A. But
if the dose remains below 40 U for more than X days, then the
patient should switch back to Pen A.
[0438] Patients who started treatment with Pen A and require a
daily dose of insulin glargine above 40 U will be switched to Pen
B.
[0439] The lixisenatide dose is increased or decreased along with
insulin glargine dose changes and also depends on which Pen (A or
B) is used. For example, when the dose window in pen A (ratio of
2:1) shows 30 U, this is a dose of 30 U of insulin glargine and 15
.mu.g of lixisenatide, while for pen B (ratio of 3:1) when the dose
window shows 30 U, this is a dose of 30 U of insulin glargine and
10 .mu.g lixisenatide. Detailed doses for pen A and pen B are shown
in FIG. 16.
Insulin Glargine Only (Lantus.RTM.SoloStar.RTM.)
[0440] Disposable pre-filled pen-injectors Lantus.RTM.
SoloSTAR.RTM. are provided to all patients at V2 and to patients
randomized to the insulin glargine arm at V6 (week 0, Day 1) and
thereafter. Each pen is specifically labeled for use in the study
and contains 300 units insulin glargine in 3 ml. Doses can be set
from 1 to 80 units in steps of 1 unit. However, in this study the
maximum daily dose of insulin glargine is 60 U.
7.2.2.2 Training for Injection Devices
[0441] An instruction leaflet (including IMP leaflet?) will be
provided which explains how to use the disposable pen-injectors.
All patients will be trained by study staff in how to use the pen
correctly, how to store it and how to change the needle for both
the following pen-injector devices [0442] At V2 (week -6): all
patients are trained using a training disposable Lantus.RTM.
Solostar.RTM.. [0443] At V6 (day 1): Patients who are randomized to
receive the combination treatment are trained using a training
disposable pen A and pen B.
[0444] Training will be repeated as often as deemed necessary by
study site staff during the run-in phase and the treatment
period.
[0445] The pens and leaflet that the patient will need to use
during the run-in phase and treatment period will be dispensed
according to the visit. Each patient is supplied with the
appropriate number of pen-injectors according to the dispensing
scheme indicated in the study flowchart (see Section 1.2).
[0446] The following commercial pen needles will be provided for
use with the disposable injection pen devices: [0447] BD
Micro-Fine+31 G.times.8 mm
[0448] Pen-device related issues (malfunctions) should be reported
to the sponsor on a Product
[0449] Technical Complaint (PTC) form, which is described in a
separate manual.
7.2.3 Dosage Schedule
[0450] Insulin glargine/lixisenatide fixed ratio combination
[0451] The insulin glargine/lixisenatide fixed ratio combination
should be self-administered once daily in the morning the hour (0
to 60 minutes) before breakfast, using Pen A or Pen B depending on
the daily dose of insulin glargine.
Insulin Glargine
[0452] The insulin glargine should be self-administered once daily
at any time of the day but at approximately the same time every
day, using the Lantus.RTM. SoloSTAR.RTM., during the run-in phase
(all patients) and the open-label randomized treatment period (only
for patients randomized to insulin glargine). The injection time
will be selected at the discretion of patients and investigators at
V2.
Injection Site
[0453] The IMP should be administered by deep subcutaneous
injection, alternating between the left and tight anterolateral and
left and right posterolateral abdominal wall or thighs or upper
arms. Within a given area, location should be changed (rotated) at
each time to prevent injection site skin reactions.
[0454] At days of on-site visits, the IMP which is to be
administered before breakfast should be self-administered at the
investigational site under the observation of site staff.
7.2.4 Starting Dose and Dose Adjustments
7.2.4.1 During Run-in Phase
Starting Dose of Insulin Glargine
[0455] From the start of run-in (visit 2), the only basal insulin
allowed is insulin glargine. Patients receiving any basal insulin
other than insulin glargine before screening will switch to once
daily insulin glargine at visit 2.
[0456] Guidelines for transitioning patients' basal insulin doses
from their pre-study to study regimens at V2 are offered below.
These are guidelines only, and other changeover regimens may be
employed if desired. [0457] Patients should be informed at the time
of the screening visit (V1) not to administer the morning dose of
basal insulin at the day of V2, if at all possible. [0458] Patients
receiving more than 1 daily injection of basal insulin will change
to one daily injection at V2. [0459] The total basal insulin dose
on the day before V2 will be used for the calculation of the
starting dose according to the rules described in Table 1.
TABLE-US-00004 [0459] TABLE 1 Starting dose of insulin glargine at
run-in visit The daily dose (U) of Patients on glargine insulin
will be equal Insulin glargine the total daily dose on the day
prior to the visit 2 Basal insulin other than insulin the total
daily dose on the day glargine once daily prior to the visit 2
Basal insulin other than insulin 80% of total daily dose(=total
glargine more than once daily daily dose reduced by 20%) on the day
prior to the visit 2
[0460] Insulin glargine can be injected at any time of the day but
at the same time every day. The time of the once daily injection is
at the discretion of the patient and investigator and will be
decided at Visit 2 and should remain about the same throughout the
study (during the run-in phase for all patients, and during the
randomized treatment period for patients randomized to insulin
glargine).
Adjustment of Insulin Glargine Dose
[0461] Doses will be adjusted based on daily measured fasting SMPG
with the goal of improving fasting glycemic control and allowing
patients to meet the randomization criteria (HbA1c at visit
5.gtoreq.7% and .ltoreq.10%; mean fasting SMPG.ltoreq.140 mg/dL
[7.8 mmol/L] measured for the 7 days before visit 6). The titration
procedure to meet these criteria while avoiding hypoglycemia is at
the discretion of the Investigator. Small decreases in dose are
permitted if there is hypoglycemia, again at the discretion of the
Investigator.
7.2.4.2 During Open-Label Randomized Treatment Period
7.2.4.2.1 Insulin Glargine/Lixisenatide Fixed Ratio Combination
Group
Patients Who Received Insulin Glargine (Lantus.RTM.) in the Morning
During the Run-in Phase:
[0462] Patients having the day before Visit 6 (D-1) a daily insulin
glargine dose of [0463] <30 U will start the combination
treatment with pen A at a dose of 20 U of insulin glargine/10 .mu.g
of lixisenatide [0464] .gtoreq.30 U will start the combination
treatment with pen B at a dose of 30 U of insulin glargine/10 .mu.g
of lixisenatide
[0465] The first injection will be done on site the morning of the
randomization.
[0466] Patients who received insulin glargine at a time of day
other than the morning, during the run-in phase:
[0467] These patients will have to switch to administration within
the hour before breakfast. A procedure for transitioning time
administration is offered below, but other changeover regimens may
be employed if desired: [0468] The morning of the baseline visit
after randomization (D1): injection while patient is on site, of an
insulin glargine dose equal to -1/2-2/3 (to be decided by the
investigator) of the dose injected the day before randomization
(D-1) [0469] The next morning (D2), patients having the day before
Visit 6 (D-1) a daily insulin glargine dose of [0470] <30 U will
start the combination treatment with pen A at a dose of 20 U of
insulin glargine/10 .mu.g of lixisenatide. [0471] .gtoreq.30 U will
start the combination treatment with pen B at a dose of 30 U of
insulin glargine/10 .mu.g of lixisenatide.
[0472] For all patients this first dose (either 20 U/10 .mu.g or 30
U/10 .mu.g) will be maintained stable for 2 weeks. For the next two
weeks, any necessary dose increase will be limited to a maximum of
+2 U not more often than once a week.
[0473] After the first 4 weeks, the doses will be titrated once a
week according to the algorithm described in table 2 until the
patient reaches a target fasting SMPG (80 to 100 mg/dL [4.4 to 5.6
mmol/L]) without hypoglycemia. Thereafter, until the end of the
study, the dose will be adjusted as needed to maintain these
fasting SMPG targets.
[0474] Patients who started the fixed ratio combination treatment
using Pen A and then need a daily dose>40 U will be instructed
to switch from Pen A to Pen B: e.g a patient receiving 40 U with
pen A and having a median of fasting self-monitored plasma glucose
(SMPG) values from preceding 3 days>140 mg/dL (>7.8 mmol/1)
would need a dose adjustment of +4 U/day (according to table 1) to
a daily dose of 44 U. Since the maximum dose to be delivered with
Pen A is 40 U, the patient will use Pen B to self-inject the
adjusted 44 U daily dose.
TABLE-US-00005 TABLE 2 Dose adjustment algorithm Median of fasting
SMPG values from Insulin glargine dose preceding 3 days
adjustments(U/day)* >140 mg/dL (>7.8 mmol/L) +4 >100 and
.ltoreq.140 mg/dL (>5.6 and .ltoreq.7.8 +2 mmol/L) Glycemic
target: 80 and 100 mg/dL (4.4 and No change 5.6 mmol/L), inclusive
.gtoreq.60 and <80 mg/dL (.gtoreq.3.3 and <4.4 mmol/L) -2
<60 mg/dL (<3.3 mmol/L) or occurrence of 2 -2 to -4 or at the
(or more) symptomatic hypoglycemic discretion of the episodes or
one severe hypoglycemic investigator episode (requiring assistance)
documented or medically in the preceding week. qualified designee
*Dose adjustment should not be done more than once weekly.
7.2.4.2.2 Insulin Glargine Group
[0475] Time of injection should remain the same as determined at
visit 2 for the run-in phase.
[0476] Patients randomized to insulin glargine will administer the
same daily dose of insulin glargine on the day of randomization as
the day before randomization, and then conduct insulin dose
titration as necessary during the open-label randomized treatment
period.
[0477] The dose will be titrated once a week following the same
algorithm as the fixed ratio combination group (table 2), until the
patient reaches the target fasting SMPG (80 to 100 mg/dL [4.4 to
5.6 mmol/L]) without hypoglycemia. Thereafter, until the end of the
study, the dose will be adjusted as needed to maintain these
fasting SMPG targets.
7.2.4.2.3 in Both Groups
[0478] Dose changes are based on a median of fasting SMPG values
from last 3 days measured by the patient using glucometers and
accessories supplied by the sponsor for this purpose.
[0479] The total daily insulin glargine dose will be capped at 60
U. If a dose>60 U of insulin glargine is needed to maintain
HbA1c below predefined thresholds value, the dose should be kept at
60 U and a rescue therapy should be introduced (see Section 7.4).
All assessments planned at the end of treatment visit must be
performed before initiating rescue therapy.
[0480] Sound clinical judgment is to be exercised while titrating
patients. Investigators may adjust or stop titration, or
temporarily reduce dose if they believe further titration would be
hazardous at that time.
[0481] Patients will be educated about the titration schedule so
that they can monitor it with the assistance of the investigator or
medically qualified designee. Patients will be allowed to increase
the dose by themselves if necessary (i.e. median of fasting SMPG
values from preceding 3 days>100 mg/dL), but not by more than +2
U and not more often than once a week. All other dose increases
must be discussed between the patient and appropriate site
personnel. All discussions must be properly documented in the
patient's record. If needed, additional contacts will be made
available for patients to discuss dose adjustments in between the
scheduled visits. It is at the discretion of the investigator to
allow well-trained patients to IMP insulin dose adjustments in
between scheduled visits without prior consultation of the site
personnel.
[0482] Doses may be reduced or modified at any time for
hypoglycemia and according to the medical judgment of investigator.
Patients who experience mild to moderate hypoglycemia as a result
of a missed meal, unusual exercise or alcohol use will be advised
how to correct their behaviour and will not necessarily have their
insulin dose decreased (decision to be based on investigators
clinical judgment).
7.3 Noninvestigational Medicinal Products
[0483] Metformin (If appropriate) is considered as a
non-investigational medicinal product (NJMP). It (commercial
metformin tablet) will be administered orally according to its
locally approved label.
[0484] If patients are on metformin as background treatment, it
should be at a stable dose of at least 1500 mg/day or maximal
tolerated dose for at least 3 months prior to screening. This
should be continued and the dose should remain stable throughout
the study unless there is a specific safety issue related to this
treatment. Sulfonylureas, glinides, SGLT-2i and DPP-4i, if
previously taken, will be stopped at the start of run-in (Visit 2)
and cannot be used during the run-in phase and the treatment
period.
[0485] Rescue therapy (Section 7.4) if appropriate will be
considered as
[0486] NIMP(s) Metformin treatment dose or rescue therapy is to be
reported in the e-CRF.
[0487] The cost of the background treatment metformin (if
applicable) or rescue therapy not covered by health insurance will
be reimbursed where permitted by local regulations.
7.4 Rescue Therapy
[0488] Routine fasting SMPG and central lab alerts on FPG (and
HbA1c after week 12) are required to ensure that glycemic
parameters remain under predefined thresholds values (see below).
If all the fasting SMPG values in three consecutive days exceed the
specific limit, the patient should contact the investigator and a
central laboratory FPG measurement (and HbA1c after week 12) will
be performed.
[0489] The thresholds values are defined as follows, depending on
study period: [0490] From Visit 13 (week 8) to Visit 15 (week 12)
(excluding V15 value): FPG>240 mg/dL (13.3 mmol/L). [0491] From
Visit 15 (week 12) up to Visit 21 (week 30) (including V21 value):
FPG>200 mg/dL (11.1 mmol/L) or HbA1c>8%.
[0492] In case of FPG or HbA1c above the threshold values, the
investigator should ensure that no reasonable explanation exists
for insufficient glucose control and in particular that: [0493]
Plasma glucose was measured when patient was fasting (i.e. after at
least 8-hour fasting); [0494] Treatment is being correctly titrated
according to the protocol (up to a maximum daily dose of 60 U for
both groups); [0495] There is no intercurrent disease which may
jeopardize glycemic control (e.g. infection) [0496] Compliance to
treatment is appropriate [0497] Compliance to diet and lifestyle is
appropriate.
[0498] If any of the above can reasonably explain the insufficient
glycemic control, the investigator should undertake appropriate
action, i.e.: [0499] Assess plasma glucose in fasting condition
(i.e., after at least 8 hours fasting); [0500] Titrate insulin
glargine or insulin glargine/lixisenatide fixed ratio combination
according to the protocol (up to a maximum of 60 U for both
groups); [0501] Initiate an evaluation and treatment of any
intercurrent disease (to be reported in AE/concomitant medication
parts of the e-CRF and the medical record); Stress the absolute
need to comply with treatment; [0502] Schedule a meeting with the
patient and a qualified nutrition professional to reinforce the
absolute need to comply with diet and lifestyle recommendations;
[0503] Schedule a FPG/HbA1c assessment at the next visit (if the
next visit is a phone call, it should be replaced by an on-site
visit).
[0504] If none of the above reasons can be found, and/or
appropriate actions fail, or if a dose>60 U is necessary to
decrease FPG/HbA1c below threshold, a short/rapid-acting insulin
may be added as rescue therapy; this should be started with a
single daily administration to be given at any meal other than
breakfast in the fixed ratio combination group, and at any meal for
the insulin glargine group.
[0505] All assessments (including 2-hour standardized meal test but
except for PK and antibody assessments) planned for the end of
treatment visit are to be performed before initiating rescue
therapy. After these assessments are completed and rescue therapy
has been initiated, the patient will remain in the study and
continue with study treatment (including background therapy). The
planned visits and assessments (including PK and antibody
assessments but except for meal test, and PRO assessments) should
be performed until the last scheduled visit.
Note:
[0506] If the central laboratory results demonstrate an FPG and/or
HbA1c above threshold value(s), the investigator will receive an
alert from the central laboratory.
[0507] The decision to initiate rescue therapy should not be based
on a single laboratory value. If FPG is incidentally found above
threshold at a routine visit, the investigator should ensure that
the criteria for rescue therapy are fulfilled (i.e. 3 consecutive
fasting SMPG values above threshold confirmed by a central
laboratory value) before initiating rescue therapy.
[0508] Short-term (up to 10 days maximum) use of short/rapid-acting
insulin therapy (e.g., due to acute illness or surgery) will not be
considered as rescue therapy. All such use of short/rapid-acting
insulin therapy must be reported in the e-CRF and patient
record.
7.5 Blinding Procedures
7.5.1 Methods of Blinding
[0509] This study is an open-label design.
Compensation for Lack of Blinding:
[0510] The investigator and the Sponsor will not have access to the
data of the primary efficacy endpoint (ie, HbA1c) nor to the data
of the standardized meal test endpoints obtained after baseline
visit until V21 (week 30), or until End of Treatment visit in case
of premature treatment discontinuation. However, the study team may
review the data for the primary efficacy parameter in descriptive
statistics with the name of the IMP treatment masked during data
review meetings.
[0511] ARAC, CAC, and PSAC members will review and adjudicate
events in a blinded manner (please also refer to Section 5.4).
[0512] The Data Monitoring Committee receives unblinded, closed
reports from an independent statistician for review, which have to
be handled strictly confidentially. None of these reports may be
delivered to unauthorized persons (please also refer to Section
5.4.1).
7.6 Method of Assigning Patients to Treatment Group
[0513] Patients are randomized to receive during the 30-week
open-label treatment period, once daily, either insulin
glargine/lixisenatide fixed ratio combination or insulin glargine
alone. The randomization ratio is 1:1. The randomization is
stratified by HbA1c value (<8, .gtoreq.8%) at week -1 and
screening metformin use (Y, N).
[0514] The randomization and the treatment allocation are performed
centrally by an Interactive Voice/Web Response System (IVRS/IWRS).
The randomized treatment kit number list is generated centrally by
Sanofi, and the Study Biostatistician provides the randomization
scheme (including stratification) to the IVRS/IWRS. Then, the
IVRS/IWRS generates the patient randomization list according to
which it allocates treatment arms to the patients.
[0515] The IMPs (insulin glargine/lixisenatide fixed ratio
combination or insulin glargine alone) are provided in open-label
boxes and are identified with treatment kit numbers.
[0516] At the screening visit the investigator or designee has to
contact the IVRS/IWRS center to receive the patient number. The
patient identification (patient number) is composed of 9-digit
number containing the 3-digit country code, the 3-digit center code
and the 3-digit patient chronological number (which is 001 for the
first patient screened in a center, 002 for the second patient
screened in the same center etc.).
[0517] On V6 (week 0), after V5 (week -1) assessment results are
reviewed and baseline assessments are completed, the IVRS/IWRS is
contacted for randomization and allocation of the treatment kits.
For each randomized patient, the IVRS/IWRS will allocate a
treatment kit number and a quantity of kit to be dispensed
corresponding to the same treatment arm as assigned at
randomization. After V6 (week 0) the IVRS/IWRS is contacted again
each time a new treatment kit(s) allocation is necessary. The
IVRS/IWRS will allocate treatment kits using their treatment kit
number.
[0518] A randomized patient is defined as a patient who is
registered and assigned to a randomized treatment arm by the
IVRSIIWRS, as documented from IVRS/IWRS log file.
[0519] A patient cannot be randomized more than once in the study.
Additionally, the patient cannot enter in the run-in phase more
than once.
7.7 Packaging and Labeling
[0520] Packaging is in accordance with the administration schedule.
The content of the labeling is in accordance with the local
regulatory specifications and requirements.
[0521] The appropriate number of kits will be dispensed to cover up
to the next dispensing visit. Storage conditions and use-by-end
date are part of the label text.
[0522] Treatment labels will indicate the treatment number (used
for treatment allocation and reported in the e-CRF). The patient
number, visit number and date of dispensation will be entered
manually by the site staff on the treatment box label prior to
dispensing.
Insulin Glargine/Lixisenatide Fixed Ratio Combination
[0523] Pens A containing a 3 ml solution of Insulin glargine 100
U/ml and lixisenatide 50 ug/ml are supplied as open-label treatment
kits containing 3 pre-filled pens.
[0524] Pens B containing a 3 ml solution of insulin glargine 100
U/ml and lixisenatide 33 ug/ml are supplied as open-label treatment
kits containing 3 pre-filled pens.
Insulin Glargine (Lantus.RTM. SoloSTAR.RTM.)
[0525] Insulin glargine pens (Lantus.RTM. SoloSTAR.RTM.) containing
a 3 ml solution of insulin glargine
[0526] 100 U/ml are supplied as open-label treatment kits
containing 3 Lantus.RTM. SoloSTAR.RTM. pens.
7.8 Storage Conditions and Shelf Life
[0527] Investigators or other authorized persons (eg, pharmacists)
are responsible for storing IMP in a secure and safe place in
accordance with local regulations, labeling specifications,
policies and procedures.
[0528] Control of IMP storage conditions, especially control of
temperature (eg, refrigerated storage) and information on in-use
stability and instructions for handling the Sanofi compound should
be managed according to the rules provided by the Sponsor.
[0529] The expiry date is mentioned on the IMPs labels, and storage
conditions are written on the IMPs labels and in the instruction
leaflet.
Insulin Glargine/Lixisenatide Fixed Ratio Combination
[0530] Prior to the first use, the disposable fixed ratio
combination pens have to be stored between +2.degree. C. and
+8.degree. C., protected from light, and must not be frozen.
[0531] In-use disposable pen-injector has to be stored below
+30.degree. C. (not refrigerated) protected from light. Each pen
should be replaced if not completely used within 14 days.
Insulin Glargine (Lantus.RTM. SoloSTAR.RTM.)
[0532] Prior to the first use, the disposable Lantus.RTM.
SoloSTAR.RTM. pens have to be stored between +2.degree. C. and
+8.degree. C., protected from light, and must not be frozen.
[0533] In-use disposable Lantus.RTM. SoloSTAR.RTM. pens have to be
stored below +25.degree. C. (not refrigerated) protected from
light. Each pen should not be used for more than 28 days after the
first use.
7.9 Responsibilities
[0534] The Investigator, the hospital pharmacist, or other
personnel allowed to store and dispense the IMP will be responsible
for ensuring that the IMP used in the clinical trial is securely
maintained as specified by the Sponsor and in accordance with
applicable regulatory requirements.
[0535] All IMPs will be dispensed in accordance with the
Investigator's prescription and it is the Investigator's
responsibility to ensure that an accurate record of IMP issued and
returned is maintained.
[0536] Any quality issue noticed with the receipt or use of an IMP
(deficiency in condition, appearance, pertaining documentation,
labeling, expiration date, etc) should be promptly notified to the
Sponsor. Some deficiencies may be recorded through a complaint
procedure.
[0537] A potential defect in the quality of IMP may be subject to
initiation of a recall procedure by the Sponsor. In this case, the
Investigator will be responsible for promptly addressing any
request made by the Sponsor, in order to recall IMP and eliminate
potential hazards.
[0538] Under no circumstances will the Investigator supply IMP to a
third party, allow the IMP to be used other than as directed by
this clinical trial protocol, or dispose of IMP in any other
manner.
7.9.1 Treatment Accountability and Compliance
[0539] The investigator checks the compliance to the study
treatments based on the patient diary and by visually checking the
returned fixed ratio combination pens or Lantus.RTM. SoloSTAR.RTM.
pens and completes the appropriate "Treatment Log Form". Visual
check on return has to be performed by site staff. In addition
he/she also records the dosing information on the appropriate pages
of the e-CRF.
[0540] For metformin (if appropriate), name, start and end date of
treatment, total daily dose, etc, will be documented in the source
documents. Compliance to metformin (if appropriate) will be checked
by interviewing the patient and reviewing diary at each visit and
be documented in the source documents and in the e-CRF.
7.9.2 Return and/or Destruction of Treatments
[0541] Patients have to return used and in-use IMPs (and
corresponding leaflets if appropriate) at each on-site visit.
Patients also return unused IMPs each time a re-supply is planned
(see Section 1.2).
[0542] Patients have to return used, in-use and unused IMP at Visit
21 (or final assessment on-treatment visit in case of permanent
premature discontinuation).
[0543] All partially used or unused treatments will be retrieved by
the Sponsor. A detailed treatment log of the returned IMP will be
established with the Investigator (or the pharmacist) and
countersigned by the Investigator and the Monitoring Team.
[0544] For NIMP not provided by the sponsor, tracking and
reconciliation has to be achieved by the investigator according to
the system proposed by the sponsor.
7.10 Concomitant Medication
[0545] A concomitant medication is any treatment received by the
patient concomitantly to any open-label IMP. (medications should
also be reported during screening period and follow-up).
7.10.1 Allowed Concomitant Therapy
[0546] Any therapies or medications other than prohibited
concomitant therapy in addition to the IMP should be kept to a
minimum during the study. However, if these are considered
necessary for the patients welfare and are unlikely to interfere
with the IMP, they may be given at the discretion of the
investigator, with a stable dose (when possible).
[0547] In the insulin glargine/lixisenatide fixed ratio combination
treatment group, for oral medicinal products that are particularly
dependent on threshold concentrations for efficacy, such as
antibiotics, patients should be advised to take those medicinal
products at least 1 hour before or 4 hours after lixisenatide
injection. Gastro-resistant formulations containing substances
sensitive to stomach degradation, should be administered 1 hour
before or 4 hours after lixisenatide injection.
[0548] Specific treatments, which are ongoing before the study
and/or prescribed or changed during the study, must be recorded in
the e-CRF and Source Data (please refer to Section 9.2).
7.10.2 Concomitant Diabetes Therapy
[0549] Patients are enrolled with a background therapy consisting
of a stable basal insulin regimen alone or in combination with a
stable dose for at least 3 months of 1 to 2 OADs before the
screening visit that can be: metformin (1500 mg/day or maximal
tolerated dose), a sulfonylurea (SU), a glinide, a
dipeptidyl-peptidase-4 (DPP-4) inhibitor or a SGLT-2
inhibitors.
[0550] From V2, all patients receive insulin glargine as basal
insulin.
[0551] Previous OADs (SU, a glinide, DPP-4i or a SGLT-2i) other
than metformin will be discontinued from visit 2. Iftaken, previous
treatment with metformin is to be continued throughout the study.
Metformin should be kept at stable dose throughout the study unless
there is a specific safety issue related to this treatment.
Metformin treatment dose changes are to be properly reported in
patient record and in the eCRF. (see Section 7.3).
[0552] No other concomitant antidiabetic treatments except rescue
therapy should be used in this study.
7.10.3 Prohibited Concomitant Therapy
[0553] The following drugs are not permitted during the screening
period (including screening phase and run-in phase) and the
randomized open-label treatment periods: [0554] Any
glucose-lowering agents other than the IMP, authorized background
anti-diabetic therapy (metformin if appropriate) and rescue
therapy, if necessary. [0555] Note: Short time use (10 days) of
short/rapid-acting insulin due to acute illness or surgery (eg,
infectious disease) is allowed; Sulfonylurea, glinide, SGLT-2
inhibitor or DPP-JV inhibitor if previously taken should be stopped
at V2. [0556] Systemic glucocorticoids for more than 10 days
(topical or inhaled applications are allowed), [0557] Body weight
loss drugs.
[0558] During the 3-day follow-up period, any treatments (other
than GLP-1 receptor agonists) are permitted, as deemed necessary by
the Investigator.
8 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
[0559] All biological efficacy and safety analysis will be
performed by a Central Laboratory. Detailed information on samples
drawing, management and analysis will be provided in a specific
manual.
8.1 Primary Endpoint
8.1.1 Primary Efficacy Endpoint
[0560] Change in HbA1c from baseline to week 30
8.2 Secondary Endpoints
8.2.1 Secondary Efficacy Endpoint(s)
[0561] The continuous secondary efficacy endpoints are: [0562]
Change in 2-hour PPG and in blood glucose excursion during
standardized meal test from baseline to week 30, [0563] Change in
body weight from baseline to week 30, [0564] Change in 7-point SMPG
profiles from baseline to week 30 (each time point and average
daily value), [0565] Change in daily dose of insulin glargine from
baseline to week 30; [0566] Change in FPG from baseline to week 30,
[0567] Change in 30-minute and 1-hour PPG and blood glucose
excursion during standardized meal test from baseline to week
30.
[0568] The categorical secondary efficacy endpoints are: [0569]
Percentage of patients reaching HbA1c.ltoreq.6.5% at week 30,
[0570] Percentage of patients reaching HbA1c<7% at week 30,
[0571] Percentage of patients reaching HbA1c<7% with no body
weight gain at week 30, [0572] Percentage of patients reaching
HbA1c<7% at week 30 with no documented [PG 70 mg/dL (3.9
mmoJJL)] symptomatic hypoglycemia during the 30-week randomized
treatment period, [0573] Percentage of patients reaching
HbA1c<7% with no body weight gain at week 30 and with no
documented [PG 70 mg/dL(3.9 mmol/L)] symptomatic hypoglycemia
during the 30-week randomized treatment period, [0574] Percentage
of patients requiring a rescue therapy during 30-week open-label
treatment period.
[0575] Observation period of efficacy endpoints [0576] The
on-treatment period for efficacy endpoints (primary and secondary
efficacy endpoints) is defined as the time from the first injection
of open-label IMP up to 14 days for HbA1c; 0 day for standardized
meal test parameters, 7-point SMPG and insulin glargine dose; 1 day
for FPG; and 3 days for body weight after the last injection of IMP
or up to the introduction of rescue therapy, whichever is the
earliest.
[0577] The baseline value for efficacy endpoints is the last
available value prior to the first injection of IMP.
8.2.2 Safety Endpoints
[0578] The safety endpoints are assessed by: [0579] Symptomatic
hypoglycemia (documented, probable, severe symptomatic
hypoglycemia), [0580] Adverse events, serious adverse events and
AESI, Safety laboratory values, [0581] Vital signs and physical
examination, [0582] Electrocardiogram (ECG), [0583] Immunogenicity
(Antibody variables): Anti-lixisenatide antibodies and/or
anti-insulin antibodies (fixed ratio combination group).
Observation Period of Safety Endpoints
[0584] The observation period of safety data will be divided into 3
segments: [0585] The pre-treatment period is defined as the time
between the date of the informed consent and the first injection of
open-label IMP. [0586] The on-treatment period is defined as the
time from the first injection of open-label IMP up to 3 days (1 day
for symptomatic hypoglycemia) after the last injection of IMP,
regardless of the introduction of rescue therapy. The 3-day
interval is chosen based on the half-life of the IMP (approximately
5 times the half-life of lixisenatide). [0587] The post-treatment
period is defined as the time starting 4 days after last injection
of open-label IMP (after the on-treatment period).
[0588] The baseline value for safety endpoints will be the last
available value prior to the first injection of IMP.
8.2.2.1 Symptomatic Hypoglycemia
[0589] Symptomatic hypoglycemia (documented, probable, severe
symptomatic hypoglycemia) will be assessed. Please refer to Section
9.6.1 for details.
8.2.2.2 Adverse Events
[0590] AE including SAE and AESI will be assessed. Please refer to
Section 9.4 to Section 9.7 for details.
[0591] Adverse event collection: Adverse events and serious adverse
events will be collected from the time of informed consent
signature and then at each visit until the end of the study.
8.2.2.3 Laboratory Safety Variables
[0592] All laboratory data listed in this section will be measured
at a central laboratory. The laboratory data will be collected at
designated visits in Section 1.2. Clinical laboratory values will
be analyzed after conversion into standard international units.
International units will be used in all listings and tables. The
conventional unit will be presented if appropriate.
[0593] The following laboratory safety variables will be analyzed:
[0594] Hematology: blood count (erythrocytes, hemoglobin,
hematocrit, leukocytes), differential blood count (neutrophils,
lymphocytes, monocytes, eosinophils, basophils) and platelets.
[0595] Clinical chemistry: total bilirubin (and, in case of values
above the normal range, differentiation in conjugated and
non-conjugated bilirubin), AST, ALT, ALP, G-GT, creatinine, uric
acid, sodium, potassium, calcium, phosphorus. [0596] Lipid
parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol,
triglycerides). [0597] Serum amylase and lipase. [0598] Serum
calcitonin. [0599] Urine albumin/creatinine ratio assessment (to be
done on first morning urine sample).
[0600] In addition, the following laboratory data will also be
collected at screening visit, baseline visit, and at on-site visits
depending on item (see Section 1.2) for identifying patients with
exclusion criteria, childbearing potential or safety consideration.
[0601] Hepatitis B surface antigen and hepatitis C antibody (only
at screening). [0602] Urine analysis (assayed by the central
laboratory): pH, glucose, ketones, leucocytes, blood/hemoglobin,
protein (only at screening). [0603] Serum pregnancy test in females
of childbearing potential. [0604] Serum FSH and estradiol (only in
females requiring confirmation of postmenopausal status, and only
at screening).
[0605] In case of suspected acute pancreatitis, safety laboratory,
including amylase and lipase should be performed in a timely
manner. Please also refer to Section 9.6.4.
[0606] For patients concomitantly treated with oral anticoagulants
the International Normalized Ratio (INR) values (measured by the
patient's usual laboratory) should be reported in the e-CRF each
time they are available associated with the actual dose of the
anticoagulant.
[0607] Notes: Any abnormal laboratory value should be immediately
rechecked (whenever possible using the central laboratory) for
confirmation before making a decision of permanent discontinuation
of IMP for the concerned patient. Please also refer to Section 9.3
and Section 9.4.2.
8.2.2.4 Vital Signs
[0608] Clinical safety will be assessed by: [0609] Physical
examination [0610] Vital signs (systolic and diastolic blood
pressure, heart rate)
[0611] Blood pressure (mmHg) should be measured when the patient is
quiet and seated and with their arm outstretched in line with
mid-sternum and supported. Measurement should be taken under
standardized conditions, approximately at the same time of the day,
on the same arm, with the same device (after the patient has rested
comfortably for at least five minutes) and the values are to be
recorded in the e-CRF. Both systolic blood pressure and diastolic
blood pressure should be recorded. Devices for blood pressure
measurement should be regularly recalibrated according to
manufacturers' instructions.
Determination of the Arm for Blood Pressure Measurements:
[0612] At visit 1 of the screening period, blood pressure has to be
measured on both of the arms after 5 minutes in seated position and
then again after two minutes in both arms in seated position. The
arm with the higher diastolic pressure will be determined at this
visit, identifying the reference arm for future measurements
throughout the study. The highest value will be recorded in the
e-CRF (all blood pressure values are to be recorded in the source
data).
[0613] Heart rate (bpm) will be measured at the time of the
measurement of blood pressure.
8.2.2.5 Electrocardiogram (ECG) Variables
[0614] The ECG assessment of "normal" or "abnormal" will be
analyzed.
[0615] ECGs are measured automatically by the device from the
investigator as automatic 12-lead ECG. ECG status of "normal" or
"abnormal" will be reported in the e-CRF as determined by the
Investigator.
[0616] The 12-lead ECGs should be performed after at least 10
minutes in supine position. The electrodes are to be positioned at
the same place for each ECG recording throughout the study.
[0617] Each trace is analyzed in comparison with the screening
recorded trace. The original trace is kept as source data.
[0618] Notes: Any abnormal ECG parameter should be immediately
rechecked for confirmation before making a decision of permanent
discontinuation of treatment with IMPs for the concerned patient.
Please also refer to Section 9.3 and Section 9.4.2.
8.2.2.6 Immunogenicity
Antibody Variables
[0619] For insulin glargine/lixisenatide fixed ratio combination
group: anti-lixisenatide antibody status (Positive, Negative) and
concentration. [0620] For both treatment groups: anti-insulin
glargine antibody status (Positive, Negative) and titer and the
change from baseline during the course of the clinical study, with
additional determination of cross reactivity to human insulin for
anti-insulin glargine positive patients.
[0621] Anti-lixisenatide antibodies and/or anti-insulin antibodies
will be measured at Day 1 and at Week 30.
Sampling Time
[0622] Blood samples for anti-insulin and anti-lixisenatide
antibody determination will be taken before injection of IMP, at
Day 1 and week 30, in both treatment groups for anti-insulin
antibody and from all patients treated with lixisenatide for
anti-lixisenatide antibody. Samples will also be taken in case of
premature discontinuation from IMP, if possible (see Section
9.3).
[0623] Note: One sample will also be taken at Week 30 (V21) for
potential additional measurements of immunogenicity.
Anti-Lixisenatide and Anti-Insulin Antibodies Handling
Procedures
[0624] Detailed procedures of sample preparation, storage and
shipment will be described in the specific laboratory manual.
Bioanalyticalmethod
[0625] Anti-insulin antibodies and anti-lixisenatide antibodies
will be determined at centralized laboratories using validated
assay methodologies.
8.3 Other Endpoint(S)
8.3.1 Pharmacokinetics
8.3.1.1 Pharmacokinetics Parameters
[0626] Total and active plasma concentrations of lixisenatide will
be assessed in the time frame from 1 to 4 hours post-injection at
Day 1 of the treatment phase and prior to injection as well as in
the time frame from 1 to 4 hours post-injection at Week 30 (for
patients in the insulin glargine/lixisenatide fixed ratio
combination).
8.3.1.2 Sampling Time
Lixisenatide PK Sampling:
[0627] For total and active concentrations of lixisenatide,
respectively, three blood samples are to be taken for patients from
the insulin glargine/lixisenatide fixed ratio combination arm: at
baseline and at end of treatment visits, as described in the
flowchart. One sample will be taken immediately before IMP
injection at week 30 and each one sample will be taken in the time
period from 1 to 4 hours post injection at Day 1 and week 30.
Samples will also be taken in case of premature discontinuation
from IMP or rescue therapy, if possible.
8.3.1.3 PK Handling Procedure
[0628] Detailed procedure of sample preparation, storage and
shipment are described in the specific lab manual.
8.3.1.4 Bioanalytical Method
Lixisenatide Total Concentration
[0629] For determination of total concentrations of lixisenatide
(bound and unbound to anti-lixisenatide antibodies) plasma samples
will be analyzed using a validated ELISA with a lower limit of
quantification of 5.5 pg/mL.
Lixisenatide Active Concentration
[0630] For determination of active concentrations of lixisenatide,
plasma samples will be analyzed using a validated cell-based assay
with a lower limit of quantification of 40 pg/mL.
[0631] Active concentrations will be analyzed for at least 100
patients from the insulin glargine/lixisenatide fixed ratio
combination although blood sample in all patients in this group
will be drawn.
8.3.2 Patient Reported Outcomes
[0632] Patient reported outcomes (PROs) questionnaires include
TRIM-D, EQ-5D and IWQoL-Lite describe further in this section.
These three PROs measures will be administered at baseline, week 12
and end of the treatment. Patient-rated and physician-rated global
treatment effectiveness evaluation scales will be administered at
the end of the study.
[0633] TRIM-D, EQ-5D and IWQoL: the patients will be requested to
complete the questionnaires by themselves during selected clinical
visits (see study flow chart) in specific booklets, independently
from Investigator, site staff and any help from friends or
relatives. For validity purposes, patients will be asked to answer
to all the questions of these questionnaires at the start of the
visit in a quiet place, and while on site to return the completed
questionnaires to the investigator or his/her designed on the same
day. Schedule of questionnaires is specified in the study flowchart
(Section 1.2). The questionnaires are shown in FIGS. 23, 24 and 25.
PROs questionnaires will be analyzed using assessments obtained
during the period from the first injection of open-label randomized
IMP up to 3 days after the last injection of IMP or up to the
introduction of rescue therapy, whichever is the earliest.
8.3.2.1 Treatment-Related Impact Measure for Diabetes (TRIM-D)
[0634] The general treatment-related impact on patients' health
related quality of life, treatment satisfaction and treatment
behavior will be assessed using the TRIM-D questionnaire.
[0635] The TRIM-D questionnaire (see FIGS. 23, 24 and 25) is a
28-item measure with 5 domains assessing Treatment Burden, Daily
Life, Diabetes Management, Compliance and Psychological Health.
This PRO measure can be scored independently for each domain or as
a total score.
[0636] The five-point Likert like response options, for all items,
range from (1) Not at all satisfied/convenient, Never to
Extremely/Almost always, Always or Extremely
dissatisfied/inconvenient to (5) Extremely satisfied/convenient,
depending upon the item stem and are scored on a scale of 0 to 100
so that a higher score indicates a better health state (less
negative impact).
[0637] The TRIM-D variables include response to each item and the
change in TRIM-D scores (total score and separate score for each of
the five domains) from baseline to endpoint.
[0638] A domain score is calculated if a respondent answers at
least half of the items in a multi-item domain (or half plus one in
the case of domains with an odd number of items).
8.3.2.2 EuroQoL Five Dimension (EQ-5D)
[0639] Patients' health related quality of life (HRQoL) will be
assessed using the EQ-5D questionnaire.
[0640] The EQ-5D questionnaire (see FIGS. 26 and 27) is a 6 item,
self-administered instrument comprised of 2 components: a
descriptive profile and a single index visual analogue scale (VAS).
The descriptive profile assesses health status on 5 dimensions:
mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression. Respondents were asked to indicate whether they
have 1) no problems; 2) some/moderate problems; or 3) extreme
problems with each of the 5 dimensions. Their responses were then
mapped to previously derived utility weights for each of the 243
possible combinations. These utility weights are intended to
represent society's ratings of the desirability of a given health
state. Utility weights have been derived from general populations
in the United Kingdom and the United States.
[0641] The VAS records the patient's personal perspective of their
current health status on a vertical rating scale with scores
ranging from 0 to 100, with 0 representing the worst imaginable
health status and 100 representing the best imaginable health
state. The VAS has been considered a representation of patients'
overall HRQoL.
[0642] The EQ-5D variables include response to each item, change in
score of the 5 dimensions from baseline to endpoint, change in
single utility index from baseline to endpoint, and change in
perceived health status on VAS from baseline to endpoint.
[0643] EQ-5D score and single utility index will be calculated only
if all 5 dimensions of the descriptive profile are responded
correctly.
8.3.2.3 Impact of Weight on Quality of Life-Lite (IWQOL-Lite)
[0644] Patients' weight related quality of life will be assessed
using the IWQOL-Lite questionnaire.
[0645] IWQOL-Lite questionnaire (see FIGS. 28 and 29) is a 31-item
self-reported instrument that reliably measures how a patient's
weight affects his/her quality of life. The five domains of the
IWQOL-Lite are physical function, self-esteem, sexual life, public
distress, and work. IQWOL-Lite scores (total score and separate
scores for each of the five domains) range from 0 to 100, with 0
representing the worst outcome and 100 representing the best.
[0646] The IQWOL-Lite variable includes response to each item and
the change in IWQOL-Lite scores (total score and separate score for
each of the five domains) from baseline to endpoint.
[0647] The score for each domain is calculated only if a respondent
answers at least half of the items in a multi-item domain (or half
plus one in the case of domains with an odd number of items), and
for the total score only if 75% of the items answered.
8.3.2.4 Patient- and Physician-Rated Global Evaluation Scales
[0648] Patient and physician-rated global treatment effectiveness
evaluation scales are self-administered instruments that will be
measuring whether patient's overall response to treatment is
excellent, good, moderate, poor or whether the patient's condition
is worsening. The variables related to these patient-rated and
physician-rated global treatment effectiveness scales include the
response to each question at end of treatment.
8.3.3 Pharmacogenetic Assessment
[0649] Pharmacogenetic sampling is optional for the patient. For
those patients who signed the specific informed consent form, a
single blood sample of 6 ml will be collected preferably at
baseline (V6; Day 1), but the sample could also be collected at any
later visit.
[0650] The data from genetic material can be used to determine a
possible relationship between genes and responses to treatment with
lixisenatide. DNA will be stored for up to 15 years from the
completion of the Clinical Study Report.
[0651] Procedures for sampling, storage and shipping of
pharmacogenetic samples are described in a specific document
included in the central laboratory manual.
[0652] The Sponsor has included safeguards for protecting patient
confidentiality. The blood sample and DNA that is extracted will be
assigned a second number, a Genetic ID (de-identification code)
that is different from the Subject ID. This "double coding" is
performed to separate a patients medical information and DNA data.
The clinical study data (coded by Subject ID) will be stored in a
distinct database at a different location from the database
containing the pharmacogenetic data (coded by Genetic ID). The key
linking Subject ID and Genetic ID will be maintained by a third
party, under appropriate access control. The matching of clinical
data and pharmacogenetic data, for the purpose of data analysis,
will be possible only by using this key, which will be under strict
access control. All data will be reported only in coded form in
order to maintain confidentiality.
8.4 Efficacy Assessment Methods
8.4.1 HbA1c Measurement
[0653] For the eligibility and efficacy assessments of the study,
HbA1c is measured by a certified level I "National Glycohemoglobin
Standardization Program" (NGSP) central laboratory.
8.4.2 Standardized Meal Test
[0654] Patients will undergo a standardized meal challenge to
assess fasting and postprandial glucose (central laboratory), as
well as plasma glucose excursion.
[0655] The standardized meal contains approximately 600 kcal and is
composed of 50 to 55% carbohydrate, 15 to 20% protein and 25 to 30%
fat.
[0656] The composition and the quantity of the standardized meal
must be identical throughout the study. If the patient needs to
receive a rescue antidiabetic medication, the standardized meal
test should be performed before the introduction of the rescue
medication and will not be performed at the final on-treatment
visit.
[0657] In case of permanent discontinuation of the treatment with
IMP, the standardized meal test should be performed only in case
the patient receives IMP, on the day of the visit.
[0658] On the day of the standardized meal test, the patients will
come to the investigational site in the morning, in fasting
conditions for at least 8 hours and must not eat any food or drink,
except water, before the scheduled standardized meal test.
Injection of insulin glargine/lixisenatide fixed ratio combination
at V21 (week 30) should be done at the investigational site in the
presence of the investigational staff 30 minutes before the start
of the standardized meal. Patient in insulin glargine group will
inject their insulin glargine at their usual injection time.
[0659] The standardized meal for all patients should be consumed
within a 15-minute period. Blood for plasma glucose is drawn 5
times: [0660] 30 minutes prior to the start of the meal and before
IMP administration if the IMP is injected before breakfast; [0661]
Just before the start of the standardized meal (0 minute), [0662]
30 minutes after the start of the standardized meal, [0663] 60
minutes after the start of the standardized meal, [0664] 120
minutes after the start of the standardized meal.
[0665] The exact times of the IMP injection and the standardized
meal intake and the blood draws are to be documented.
8.4.3 Self-Monitored Plasma Glucose Profiles (SMPG) and Glucometer,
Patient's Diaries and Training
8.4.3.1 Self-Monitored Plasma Glucose Profiles (SMPG)
[0666] SMPG measurements include the followings:
Fasting SMPG:
[0667] Fasting SMPG will be used by the investigator and patients
if appropriate to titrate and adjust insulin glargine dose or the
combination dose and to monitor glycemic control (Section 8.4). The
fasting SMPG should be measured by the patient before breakfast and
before the administration of the glucose-lowering agents (IMP or
metformin if appropriate) once a day from visit 2 to the end of the
treatment.
[0668] Daily fasting SMPG values should be recorded in patient
diary. The following daily fasting SMPG values will be entered in
the e-CRF: [0669] The values on the last 3 days leading to insulin
dose change [0670] The values measured during 7 days the week prior
to visit 6 (used to assess eligibility for randomization).
7-Point SMPG Profile:
[0671] The 7-point SMPG profile should be measured at the following
7 points: pre-prandial and 2 hours postprandial for breakfast,
lunch, dinner and at bedtime. Two hours postprandial (breakfast,
lunch and dinner) is defined as 2 hours after the start of the
meal.
[0672] The patients are requested to perform 7-point SMPG profile
measurement over a single 24-hour period on 2 different days in the
week before V6 (week 0), V15 (week 12), and V21 (week 30, end of
treatment assessment visit). All SMPG values measured on these days
will be recorded in diary and transferred into the e-CRF.
[0673] On the 7-point profile days, information on times of meals
and bedtime, injection time and doses of IMP should be recorded in
the patient's diary and entered in the e-CRF.
SMPG During Episodes of Symptomatic Hypoglycemia:
[0674] Whenever the patient feels hypoglycemic symptoms, plasma
glucose should be measured by the patient (or others, if
applicable), if possible. Patients should be instructed to measure
plasma glucose levels prior to the administration of glucose or
carbohydrate intake whenever symptomatic hypoglycemia is suspected
(Section 9.6.1), unless safety considerations necessitate immediate
glucose/carbohydrate rescue prior to confirmation. The SMPG values
are to be entered in the patient's diary and entered in the
e-CRF.
Further SMPG:
[0675] The investigator may decide to request more frequent
self-monitoring of plasma glucose if he/she considers necessary for
the patient. The SMPG values are to be entered in the patients
diary.
8.4.3.2 Glucometer, Patient's Diaries and Training
[0676] All the patients are supplied with a glucometer, the
corresponding supplies (lancets, test strips, etc.), a leaflet, and
with diaries at visit V2 (week-6) in order to perform
self-measurement of plasma glucose and its recording. The patients
will be instructed to bring their glucometers and patient diaries
with them to each site visit.
[0677] The glucometers should be calibrated according to
instructions given in the package leaflet and the study site should
also check the glucose meters regularly using the provided control
solutions for data validity.
[0678] At visit V2 (week -6) patients are trained to accurately
measure plasma glucose values with the glucometer and to correctly
record the values and other requested information in the patient's
diaries. It is the investigators responsibility to explain the need
to measure glucose at the times requested and to correctly record
all SMPG values in the patient's diaries to patients. Training is
repeated as often as necessary at the study visits.
[0679] Instruction on how to complete the patient diary on a daily
basis will be done by site staff. At each on site visit: [0680] The
study site staff reviews the patient's diary, [0681] SMPG values
stored in the glucose meter memory will be downloaded, printed out,
dated, signed and filed into the patient file. This information
will help the Investigator to assess treatment effects, adjust
insulin doses and compliance.
[0682] Note: The SMPG values recorded into the diary, which have to
be entered in the e-CRF, have to be checked for consistency with
the information from the glucose meter.
[0683] In case of inconsistency, the reason for inconsistency has
to be documented. If needed, the resulting action (e.g., training
of the patient on correct documentation of the values) is also to
be documented. The confirmed values will be entered into e-CRF by
the investigator or designee based on the glucometer output
values.
[0684] The patient diary includes but not limited to the following
information: [0685] Time and dose of IMP (insulin
glargine/lixisenatide combination or insulin glargine) injections,
[0686] Missed IMP injection (including start date and end date).
[0687] Time and value of fasting SMPG, [0688] Time of start of
meals and SMPG measurements as well as plasma glucose values the
day of the 7-point profile, [0689] Potential changes in metformin
treatment, [0690] Adverse events, including signs and symptoms
suggesting occurrence of hypoglycemia and local injection site
reactions, if any.
8.4.4 Body Weight
[0691] Body weight should be obtained with the patient wearing
undergarments or very light clothing and no shoes, and with an
empty bladder. The same scale should be used throughout the study,
and calibrated on a regular basis as recommended by the
manufacturer.
[0692] The use of balance scales is recommended; if digital scales
are used, testing with standard weights is of particular
importance. The floor surface on which the scale rests must be hard
and should not be carpeted or covered with other soft material. The
scale should be balanced with both weights at zero and the balance
bar aligned. The patient should stand in the center of the platform
as standing off-center may affect measurement. The weights are
moved until the beam balances (the arrows are aligned). The weight
is read and recorded in the e-CRF and Source Data. Self-reported
weights are not acceptable; patients must not read the scales
themselves.
8.4.5 Dose of IMP
[0693] The patients document daily their IMP dose or any missed IMP
injection in the patient diary. The following values will be
entered in the e-CRF: [0694] The daily doses of IMP used on last 3
days per week until week 12 and then the dose used in the last 3
days before each visit (including each phone call visit); [0695]
The daily doses of IMP used on the 7-point blood glucose profile
days; [0696] Missed IMP injections
[0697] In case of premature discontinuation or rescue therapy, data
on the last 3 days in the week before the time of discontinuation
or rescue therapy should be entered in the e-CRF.
8.4.6 Fasting Plasma Glucose
[0698] FPG is measured at a central laboratory. At V5 and V21, FPG
will be part of the standardized meal test.
8.5 Appropriateness of Measurements
[0699] The combination of basal insulin with a GLP-1 receptor
agonist (GLP-IRA) is expected to lower HbA1c, as a complementary
action on both fasting and postprandial glucose, with no weight
gain or even weight loss, and a limited increased risk of
hypoglycemia in a single daily injection.
[0700] The primary efficacy analysis of this study comparing
insulin glargine fixed ratio combination to insulin glargine will
be based on primary variable: change in HbA1c from baseline to week
30.
[0701] The concentration of HbA1c reflects the glycemic history of
the previous 120 days and is thus an index of mean glycemia,
documenting glycemic control over the past 2- to 3-month period.
HbA1c has also been shown to correlate with the development of
long-term complications of diabetes, and reduction of HbA1c is
known to reduce the risk of long-term microvascular complications.
Therefore, HbA1c is considered to be an appropriate primary
endpoint for assessing the effect of a treatment on glycemic
control. In addition to the analysis of the change from baseline in
HbA1c, the responder analysis allows the clinical relevance of the
reduction observed in HbA1c to be demonstrated. The duration of
study treatment is considered to be sufficient for achieving stable
conditions with IMP after titrating insulin dose and for enabling
an adequate assessment of time-dependent changes in HbA1c and the
concomitant risk of hypoglycemia.
[0702] The problem of weight gain in type 2 diabetes is widely
recognized. More than 80% of individuals with type 2 diabetes are
overweight, many at the time of diagnosis. Consequently, iatrogenic
weight gain is not only unwelcome, but represents an important
clinical issue that can become a barrier to the successful
management of glycaemic control. Body weight control is one of the
reasons to choose a GLP-1 receptor agonist instead of rapid-acting
insulin to intensify basal insulin therapy in this overweight or
obese type 2 diabetes population. Taking into account the major
impact of insulin-related body weight gain, it seems appropriate to
include body weight change as secondary efficacy endpoint.
[0703] Insulin glargine targets primarily, although not
exclusively, fasting hyperglycemia, and lixisenatide effectively
acts on post-prandial glycemia mainly by slowing down gastric
emptying. Therefore assessment of both fasting and post-prandial
glucose (after a standardized meal) is relevant in this study.
These 2 blood glucose parameters are also considered by regulatory
agencies to be a supportive measure of efficacy of an antidiabetic
agent.
[0704] Safety will be evaluated by standard clinical and laboratory
measurements. Specific safety parameters of interest for a glucose
lowering injectable peptide such as symptomatic hypoglycemia,
injection site reactions and potential allergic reactions will also
be assessed. In addition, lixisenatide being a GLP1-receptor
agonist, pancreatic enzymes (amylase and lipase) and serum
calcitonin concentration will be monitored and reported over the
study course according to specific procedures (Section 9.6)
9 STUDY PROCEDURES
[0705] This section is to summarize information not presented in
the flow chart or in Section 9.
9.1 Visit Schedule
[0706] The visit schedule and procedures/assessments listed in the
"Study Flow Chart" in Section 1.2 are not repeated in this section.
The aim of this section is to provide details on how some of the
procedures/assessments have to be performed.
[0707] This is an outpatient study and consists of 11 on-site
visits and 11 phone-call visits. Additional, optional phone call
visits to monitor insulin titration should be scheduled whenever
considered necessary by the investigator.
[0708] The patient has to be in fasting conditions for all on-site
visits. For all these visits, the patient should be seen in the
morning, approximately at the same time, as much as possible. The
patient should take metformin treatment and inject the insulin
glargine/lixisenatide fixed ratio combination or insulin glargine
(if appropriate) at the investigational site after the fasting
blood sample has been drawn. Insulin glargine will be injected at
usual time fixed at V2 even if it falls in the period of the 8-hour
fasting.
[0709] The fasting condition is defined as an overnight fast no
less than 8 hours that consisted of no food or liquid intake, other
than water. IMP and other glucose-lowering agents (i.e. metformin
if appropriate) should be administered after fasting blood sample
is drawn for all laboratory tests on the study site.
[0710] Note: If the patient is not in fasting condition at the
visits specified above, the blood sample is not collected and a new
appointment should be given to the patient for the following day,
if possible, with instruction to be fasted.
[0711] Visit window: For the run-in phase a visit window of .+-.3
days is acceptable using the date of visit 2 as reference. During
the open-label treatment period a visit window of .+-.3 days for
visit 7 to visit 15, and .+-.5 days for visit 16 to Visit 21 is
acceptable using day 1 (the day of visit 6) as reference. A visit
window of -1 day or +3 days for the post-treatment follow-up visit
(V22) is acceptable using the day of Visit 21 as reference. If one
visit date is changed, the next visit should take place according
to the original schedule.
9.1.1 Screening Period (Week -8 to Week 0)
[0712] Only patients meeting all the inclusion criteria are
candidates for the screening. The screening period is about 8 weeks
and includes screening phase which is up to two weeks from
screening visit (VI, week -8) to run-in visit (V2, week -6) and
run-in phase which is from run-in visit (V2, week -6) to baseline
visit (V6, week 0).
[0713] Only patients who meet the inclusion criteria as noted in
Section 6.1 may be screened. It will be the investigators
responsibility to confirm the diagnosis of T2DM.
[0714] The background metformin treatment (if appropriate) at a
stable dose should be continued during the screening period.
[0715] All laboratory tests measured at a central laboratory that
are needed for checking the exclusion criteria of the patients, are
performed at the screening visit. At V2 (week -6), depending on the
availability of the laboratory parameters, eligible patients can
enter into the run-in phase. Run-in visit (V2) can be performed
less than 2 weeks after screening visit if laboratory data is
available. After the screening period, patients who meet the
selection criteria at the end of screening period as noted in
Section 6.2.4 can enter into the open-label randomized treatment
period.
9.1.1.1 On-Site Visits: V1 (Screening Visit, Week-8); V2 (Run-in
Visit, Week -6); V5 (Week -1)
[0716] For the complete list and contents of procedures/assessments
scheduled for the visits, please refer to the "Study Flow Chart" in
Section 1.2 and for detailed description of assessments to Section
8 and Section 9.6.
[0717] The details of the procedures/assessments to be performed at
on-site visits during screening period and which are not described
elsewhere are provided below:
Informed Consent
[0718] The patient will receive verbal information concerning the
aims and methods of the study, its constraints and risks and the
study duration at the screening visit. Written information will be
provided to the patient and must be signed by the patient and
investigator prior to any investigations.
[0719] Demography, diabetes and medical/surgical history,
cardiovascular & allergy history, alcohol and smoking habits,
and medications
[0720] Demography data such as birth date, gender and race will be
collected. Collection of diabetes history will include
documentation of duration of diabetes, history of microvascular
complications (retinopathy, neuropathy, and nephropathy), and
history of gestational diabetes if applicable. Medical/surgical
history including patients cardiovascular and allergy history and
patient's family allergy history will be recorded. Data for alcohol
habits during the last 12 months before screening visit and smoking
habit will be collected.
[0721] Check of previous medication refers to documentation of
medication including the glucose-lowering agents and
over-the-counter medications. In women of child-bearing potential,
the contraceptive methods have to be documented.
Diet and Lifestyle Counseling
[0722] Please see Section 7.1.
IVRS/IWRS Contact
[0723] IVRS/IWRS will be contacted for notification of screening
and patient number allocation (Section 7.6). Please note that it is
important to have the IVRS/IWRS contact before any blood sample is
drawn because the patient number is given by IVRS/IWRS and it must
be reported on the laboratory requisition forms.
Training on Self-Injection Devices and Dispensation of Insulin
Glargine:
[0724] One injection pen device with the instruction leaflet is
dispensed. The patient is instructed by the study staff how to use
properly the pen, how to store it, and instruction on
self-injection technique is also given. Please refer to Section
7.2.2
Compliance Check
[0725] Compliance check includes compliance to metformin (if
appropriate), insulin treatment, and use of glucometer, review of
daily fasting SMPG values and patient diary.
Glucometer Dispensation and Training
[0726] Please see Section 8.4.3.2
Insulin Glargine Starting Dose and Dose Adjustment
[0727] Eligible patients will enter a 6-week run-in phase with
switch to (if appropriate) and/or dose optimization of insulin
glargine (see details in Section 7.2.4).
Central Laboratory Testing
[0728] Blood sample is drawn for all central laboratory tests
needed for checking the exclusion criteria. [0729] Provide patients
with a urine container and instruct them how to collect at home in
the morning of their first morning urine and to bring the urine
sample to the site at planned visit.
[0730] An appointment is given to the patient for next visit
(on-site visit or phone call visit). Patients are instructed to
return to the site in the morning and to bring the glucose meter,
the diary and insulin glargine pens.
9.1.1.2 Phone Call Visits: V3 (Week-4) and V4 (Week 2)
[0731] The patient is called by the investigator or qualified
designee at a scheduled time. If the call has been completed by
site staff other than the investigator, the investigator has to be
consulted if AE/SAE is suspected and informed in case AE/SAE
occurred. A phone call visit can optionally be performed as a
clinical visit in case of symptomatic hypoglycemia/AE or other
reasons.
[0732] During the phone call, the following questions are to be
asked: [0733] Did you experience any new medical event, disease or
symptom since the last visit? [0734] Did you experience any changes
in a pre-existing medical condition, disease or symptom since the
last visit? [0735] Did you miss, change, take or add any
medications (including OAD if appropriate) since the last visit?
[0736] Did you experience any symptoms or events of hypoglycemic
and AE? [0737] Do you feel comfortable in handling the diary,
glucose meter and IMP injection device or do you need any more
explanation?
[0738] The phone visits will also include: [0739] Asking patient
fasting pre-breakfast SMPG and insulin dose on the last 3 days
including day of visit. [0740] Adjustment of the dose of insulin
glargine as necessary. [0741] Recording of AE and symptomatic
hypoglycemia events (if any). [0742] Recording of the use or change
of any medication.
[0743] The patient will be instructed to: [0744] Perform required
SMPG measurements [0745] Complete daily the diary. [0746]
Self-inject once daily insulin glargine at the dose prescribed by
the investigator. [0747] Contact the site in case of occurrence of
adverse event, record the event in the patients diary and return to
the site as deemed appropriate.
[0748] Give an appointment to the patient for subsequent visits
(on-site visit or phone call visit) and remind them to come fasting
if planned at next on-site visit.
9.1.2 Open-Label Randomized Treatment Period (Week 0 to Week
30)
[0749] Patients meeting all inclusion criteria and with no
exclusion criteria at the end of the screening period are eligible
to be enrolled into the open-label randomized treatment period. The
duration of the open-label treatment period is 30 weeks .+-.5 days
from baseline visit (V6, week 0) to the end of treatment visit
(V21, week 30).
[0750] Each patient self-administers IMP once daily during the
open-label treatment period. The IMP dose will be adjusted
according to fasting SMPG values documented in the patient diary
(Section 7.2.4.2).
9.1.2.1 Baseline Visit (V6, Week 0, Day 1)
[0751] For the complete list and contents of procedures/assessments
scheduled for the visit, please refer to the "Study Flow Chart" in
Section 1.2 and for detailed description of assessments to Section
8 and Section 9.6.
[0752] The details of the procedures/assessments to be performed at
this visit and which are not described elsewhere are provided
below:
[0753] At this visit, the patient must return to the investigation
site in the morning after 8 hours fasting not having injected their
insulin or administered metformin (if appropriate) at home.
Patients will visit the site with the blood glucometer, the diary,
and the used, unused and in-use pens of insulin glargine.
Compliance Check
[0754] Compliance check includes compliance to insulin glargine and
metformin treatment (if appropriate) and use of glucometer, review
of daily fasting SMPG values, and the 7-point SMPG profile and
patient diary. If patient is not compliant enough with the study
procedures, the training will be repeated by the site staff.
IVRS/IWRS Contact
[0755] After the baseline assessments are completed and eligibility
confirmed, the investigator contacts IVRS/IWRS for randomization.
The treatment arm (i.e., insulin glargine/lixisenatide fixed ratio
combination or insulin glargine) is notified by IVRS/IWRS.
Training on Self-Injection Devices and Dispensation of IMP:
[0756] Patients randomized to the combination group are instructed
by the study staff how to use
[0757] properly the combination Pen A and Pen B and to store it.
Instructions on self-injection technique are also given. Injection
pen device with the instruction leaflet is dispensed.
[0758] Patients randomized to the insulin glargine group will
continue to use the insulin glargine pen (SoloStar.RTM.). Training
on SoloStar.RTM. pen-injector might be repeated if necessary.
Injection pen device is dispensed. Please refer to Section
7.2.2.
Starting Dose and Dose Adjustment of IMP
[0759] Eligible patients will enter a 30-week open-label randomized
treatment period to receive either insulin glargine/lixisenatide
fixed ratio combination or insulin glargine (see details in Section
7.2.4).
[0760] An appointment for one week later is given to the patient
for next phone call visit.
9.1.2.2 Phone Call Visits: V7 (Week 1); V9 (Week 3); V11 (Week 5);
V12 (Week 6); V14 (Week 10); V16 (Week 15); V18 (Week 21); V20
(Week 27)
[0761] The patient is called by the investigator or qualified
designee at a scheduled time. If the call has been completed by
site staff other than the investigator, the investigator has to be
consulted if AE/SAE is suspected and informed in case AE/SAE
occurred. A phone call visit can optionally be performed as a
clinical visit in case of symptomatic hypoglycemia/AE or other
reasons.
[0762] During the phone call, the following questions are to be
asked: [0763] Did you experience any new medical event, disease or
symptom since the last visit? [0764] Did you experience any changes
in a pre-existing medical condition, disease or symptom since the
last visit? [0765] Did you miss, change, take or add any
medications (including OAD if appropriate) since the last visit?
[0766] Did you experience any symptoms or events of hypoglycemic
and AE? [0767] Do you feel comfortable in handling the diary,
glucose meter and IMP injection device or do you need any more
explanation? [0768] Did you adjust IMP since last visit? If
appropriate, what is your IMP dose? [0769] Did you measure any
fasting SMPG value outside of the range 80 to 100 mg/dL (4.4 to 5.6
mmol/L)? [0770] Did you measure any fasting SMPG value above:
[0771] From Visit 13 (week 8) to Visit 15 (week 12) (excluding V15
value): FPG>240 mg/dL (13.3 mmol/L). [0772] From Visit 15 (week
12) up to Visit 21 (week 30) (including V21 value): FPG>200
mg/dL (11.1 mmol/L).
[0773] The phone visits will also include: [0774] Asking patient
fasting pre-breakfast SMPG and insulin dose on the last 3 days
including day of visit. [0775] Adjustment of the dose of IMP
(insulin glargine or insulin glargine/lixisenatide combination) to
continue treatment toward the target fasting SMPG between 100 and
80 mg/dL (5.6 and 4.4 mmol/I), inclusive. [0776] Recording of AE
and symptomatic hypoglycemia events (if any). [0777] Recording of
the use or change of any concomitant medication.
[0778] The patient will be instructed to: [0779] Perform required
SMPG measurements [0780] Complete daily the diary. [0781]
Self-inject once daily IMP at the dose prescribed by the
investigator. [0782] Contact the site in case of occurrence of
adverse event, record the event in the patient's diary and return
to the site as deemed appropriate.
[0783] Give an appointment to the patient for subsequent visits
(on-site visit or phone call visit) and remind them to come fasting
if planned at next on-site visit.
9.1.2.3 On-Site Visits: VB (Week 2); V10 (Week 4); V13 (Week 8);
V15 (Week 12); V17 (Week 18); V19(Week 24)
[0784] For the complete list and contents of procedures/assessments
scheduled for the visits, please refer to the "Study Flow Chart" in
Section 1.2 and for detailed description of assessments to Section
8 and Section 9.6.
[0785] The details of the procedures/assessments to be performed at
visits and which are not described elsewhere are provided
below.
Compliance Check
[0786] Compliance check includes compliance to IMP and metformin
treatment (if appropriate) and use of glucometer, review of daily
fasting SMPG values, and the 7-point SMPG profile and patient
diary. If patient is not compliant to the study well, the training
has to be repeated by the site staff.
[0787] Patients are instructed to return to the site in the morning
in fasting condition for all on-site visit with the glucose meter
and the diary for each on-site visit. Patients will return used
pens/in-use pens at each on-site visit and with the unused pens for
the visits where a re-supply is planned.
[0788] Upon completion of each on-site visit, an appointment for
the next visit (on-site visit or phone call visit) will be
made.
9.1.2.4 Final On-Treatment Assessment/End of Treatment Visit (V21,
Week 30)
[0789] For the complete list and contents of procedures/assessments
scheduled for the visit, please refer to the "Study Flow Chart" in
Section 1.2 and for detailed description of assessments to Section
8 and Section 9.6.
[0790] The same procedures/assessments including IVRS/IWRS contact
as planned at Visit 21 (week 30) have to be performed in case of
prematurely permanent treatment discontinuation (Section 9.3.2).
The IVRS/IWRS has to be contacted in order to register the end of
treatment.
[0791] An appointment for the post-treatment follow-up phone call
visit will be made.
9.1.3 Post-Treatment Follow-Up Phone Call Visit (V22)
[0792] Following the last injection of insulin glargine or insulin
glargine/lixisenatide fixed ratio combination either as scheduled
or prematurely, a post-treatment follow-up visit is performed 3
(-1/+3) days. This visit can be a phone call visit, or an on-site
visit in case of ongoing or new adverse event during the
post-treatment period, if necessary.
[0793] The patient is called by the investigator or medically
qualified designee at certain, previously agreed time point.
[0794] During the phone call, the following questions are to be
asked: [0795] Did you experience any new medical event, disease or
symptom since the last visit? [0796] Did you experience any changes
in a pre-existing medical condition, disease or symptom since the
last visit? [0797] Did you change, take or add any new medications
since the last visit?
[0798] All reports of hypoglycemic events (if any) or any adverse
events are recorded. The use or change of any concomitant
medications, including rescue therapy, is recorded.
[0799] IVRS/IWRS is contacted for notification of the end of
study.
9.2 Definition of Source Data
9.2.1 Source Data to be Found in the Patient's Files
[0800] Evaluations that are reported in the e-CRF must be supported
by appropriately signed identified source documentation related but
not limited to the following: [0801] Agreement and signature of
informed consent mentioning the study identification, [0802]
Patient identification, last participation in a clinical trial,
medical history, associated diseases, and data related to the
studied pathology, [0803] Contraception method for women of
childbearing potential, [0804] Reason for lack of childbearing
potential for concerned women (e.g. postmenopausal, history of
hysterectomy) [0805] Previous and concomitant medication (including
background metformin and rescue therapy), [0806] Study
identification, [0807] Treatment kit number, dates of
administration and doses of insulin glargine/lixisenatide fixed
ratio combination or insulin glargine alone (Lantus.RTM.
Solostar.RTM. pen, pen A and pen B), [0808] Compliance to metformin
if appropriate assessed by interview and patient's diary [0809]
Dates of visits and assessments including the examination report,
[0810] Vital signs, height, body weight, [0811] Faxed central lab
reports and original report received at site (dated and signed by
the Principal Investigator or Sub-Investigator), [0812] IVRSIIWRS
confirmation notifications by fax or e-mail (screening, screen
failure, run-in, run-in failure, randomization, treatment
reallocation, treatment/study discontinuation, end of study,
treatment replacement if applicable, etc.), [0813] ECG records
signed and dated, [0814] Adverse events and follow-up: [0815] In
case of SAE, increased lipase/amylase>2 ULN, increased
calcitonin the site should file in the source document at least
copies of the hospitalization reports and any relevant examination
reports (eg, imaging reports, specialists' reports, etc.)
documenting the follow-up of the SAE or AESI. [0816] Date of
premature study discontinuation (if any) and reason.
[0817] Source documentation may be found in the following: [0818]
Patients identity, [0819] Medical history, [0820] Nursing notes,
[0821] Dietician's notes, [0822] Physician's notes, [0823] Patients
diaries. [0824] Dated and signed print-outs with SMPG downloaded
from glucose meter.
9.2.2 Source Data Verification Requirements for Patients not
Randomized
[0825] For patients not randomized, the source data that must be
checked include the patient's identification details, the informed
consent signed by the patient, the study identification, the dates
of study visits and the main reasons preventing randomization.
9.3 Handling of Patient Temporary or Permanent Treatment
Discontinuation of Patient Study Discontinuation
[0826] The IMP should be continued whenever possible. In case the
IMP is stopped, it should be determined if the stop can be made
temporarily; permanent IMP discontinuation should be a last resort.
Any IMP discontinuation should be fully documented in the e-CRF. In
any case, the patient should remain in the study as long as
possible.
[0827] 9.3.1 Temporary treatment discontinuation with
investigational medicinal product(s)
[0828] Temporary treatment discontinuation may be considered by the
investigator because of suspected AEs or for other reasons. In case
of treatment interruption due to an AE, reinitiating of treatment
with the IMP will be done under close and appropriate clinical/and
or laboratory monitoring once the Investigator will have considered
according to his/her best medical judgment that the responsibility
of the IMP(s) in the occurrence of the concerned event was unlikely
and if the selection criteria for the study are still met (refer to
Section 6).
[0829] All temporary treatment discontinuation, duration should be
recorded by the Investigator in the appropriate e-CRF pages when
considered as confirmed
9.3.2 Permanent Treatment Discontinuation with Investigational
Medicinal Product(s)
[0830] Permanent treatment discontinuation is any treatment
discontinuation associated with the definitive decision from the
Investigator or the patient not tore-expose the patient to the IMP
at any time.
9.3.3 List of Criteria for Definitive Treatment Discontinuation
[0831] The patients may withdraw from treatment with IMP if they
decide to do so, at any time and irrespective of the reason, or
this may be the Investigator's decision. All efforts should be made
to document the reasons for treatment discontinuation and this
should be documented in the e-CRF.
[0832] The patients may withdraw from treatment with IMP in case of
the following: [0833] At patients own request; [0834] If, in the
Investigator's opinion, continuation with the administration of IMP
would be detrimental to the patient's well-being; [0835] At the
specific request of the Sponsor.
[0836] A patient must withdraw from treatment with IMP in either of
the following cases: [0837] Intercurrent condition that requires
discontinuation of IMP: e.g. laboratory abnormalities (see decision
tree and general guidance for the follow up of laboratory
abnormalities in Appendix B), diagnosis of acute pancreatitis
confirmed by gastroenterologic evaluation and imaging (Section
9.6.4) calcitonin value.gtoreq.50 pg/mL (see Section 9.6.6). [0838]
Pregnancy.
[0839] Any abnormal laboratory value or ECG parameter will be
immediately rechecked for confirmation before making a decision of
permanent discontinuation of the IMP for the concerned patient.
9.3.4 Handling of Patients after Permanent Treatment
Discontinuation
[0840] Patients will be maintained in the study as much as possible
and followed-up according to procedures specified in this protocol
(except 3-day safety post-treatment follow-up, PK and antibody
assessment, meal test, and PRO assessments) up to the scheduled
date of study completion, or recovery or stabilization of any AE
requiring followed-up as specified in this protocol, whichever
comes last.
[0841] If possible, after the permanent discontinuation of
treatment regardless of the reason, the patients will be as soon as
possible assessed using the procedure normally planned for the last
IMP dosing day (End of treatment visit), including PK and antibody
samples, PRO assessments, if appropriate.
[0842] Test meal will only be performed if the IMP has not been
stopped, and if the patient is not on rescue therapy. The two PK
samples normally planned for the end of treatment visit, should
only be taken if the last dose is administered at visit, otherwise
one PK sample is sufficient.
[0843] All cases of permanent treatment discontinuation should be
recorded by the Investigator in the appropriate pages of the CRF
and in the patient's medical records when confirmed. IVRS/IWRS
should be notified when a patient prematurely discontinues
treatment.
9.3.5 Procedure and Consequence for Patient Withdrawal from
Study
[0844] The patients may withdraw from the study before study
completion if they decide to do so, at any time and irrespective of
the reason. If possible, the patients are assessed using the
procedure normally planned for the end-of-study visit including PK
and antibody samples, and PRO assessments, if appropriate.
[0845] For patients who fail to return to the site, the
Investigator should make the best effort to re-contact the patient
(eg, contacting patient's family or private physician, reviewing
available registries or health care databases), and to determine
his/her health status, including at least his/her vital status.
Attempts to contact such patients must be documented in the
patients records (eg, times and dates of attempted telephone
contact, receipt for sending a registered letter).
[0846] The statistical analysis plan will specify how these
patients lost to follow-up for their primary endpoints will be
considered.
[0847] Patients who have withdrawn from the study cannot be
re-randomized (treated) in the study. Their inclusion and treatment
numbers must not be reused.
9.4 Obligation of the Investigator Regarding Safety Reporting
9.4.1 Definitions of Adverse Events
9.4.1.1 Adverse Event
[0848] An adverse event (AE) is any untoward medical occurrence in
a patient or clinical investigation patient administered a
pharmaceutical product and which does not necessarily have to have
a causal relationship with this treatment.
9.4.1.2 Serious Adverse Event
[0849] A serious adverse event (SAE) is any untoward medical
occurrence that at any dose: [0850] Results in death, or [0851] Is
life-threatening, or [0852] Note: The term "life-threatening" in
the definition of "serious" refers to an event in which the patient
was at risk of death at the time of the event; it does not refer to
an event which hypothetically might have caused death if it were
more severe. [0853] Requires inpatient hospitalization or
prolongation of existing hospitalization, or [0854] Results in
persistent or significant disability/incapacity, or [0855] Is a
congenital anomaly/birth defect [0856] Is a medically important
event [0857] Medical and scientific judgment should be exercised in
deciding whether expedited reporting is appropriate in other
situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization
but may jeopardize the patient or may require medical or surgical
intervention (ie, specific measures or corrective treatment) to
prevent one of the other outcomes listed in the definition above.
[0858] Note: The following list of medically important events is
intended to serve as a guideline for determining which condition
has to be considered as a medically important event. The list is
not intended to be exhaustive: [0859] Intensive treatment in an
emergency room or at home for: [0860] Allergic bronchospasm [0861]
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow
aplasia, myelodysplasia, pancytopenia, etc), [0862] Convulsions
(seizures, epilepsy, epileptic fit, absence, etc). [0863]
Development of drug dependence or drug abuse [0864] ALT>3
ULN+total bilirubin>2 ULN or asymptomatic ALT increase>10 ULN
[0865] Suicide attempt or any event suggestive of suicidality
[0866] Syncope, loss of consciousness (except if documented as a
consequence of blood sampling) [0867] Bullous cutaneous eruptions
[0868] Cancers diagnosed during the study or aggravated during the
study (only if judged unusual/significant by the Investigators in
oncology studies) [0869] Chronic neurodegenerative diseases (newly
diagnosed) or aggravated during the study (only if judged
unusual/significant by the Investigators in studies assessing
specifically the effect of a study drug on these diseases).
9.4.1.3 Adverse Event of Special Interest
[0870] An adverse event of special interest (AESI) is an AE
(serious or non-serious) of scientific and medical concern specific
to the Sponsors product or program, for which ongoing monitoring
and immediate notification by the Investigator to the Sponsor is
required. Such events may require further investigation in order to
characterize and understand them. AES is may be added or removed
during a study by protocol amendment.
[0871] All AESIs will be reported to the Sponsor in the same
timeframe as SAEs, ie within 24 hours as detailed in Section
10.4.1.2.
[0872] The AESIs are listed below: [0873] ALT increase (see FIG.
19) [0874] Pregnancy occurring in a female patient entered in the
study as well as pregnancy occurring in a female partner of a male
patient entered in a study with IMP/NIMP; [0875] Pregnancy will be
recorded as an AESI in all cases. [0876] It will be qualified as an
SAE only if it fulfills one of the seriousness criteria (see
Section 9.4.1.2). [0877] In the event of pregnancy in a female
participant, IMP should be discontinued. [0878] Follow-up of the
pregnancy in a female participant or in a female partner of a male
participant is mandatory until the outcome has been determined.
[0879] Symptomatic overdose (serious or non-serious) with IMP/NIMP
[0880] An overdose (accidental or intentional) with the IMP/NIMP is
an event suspected by the Investigator or spontaneously notified by
the patient (not based on systemic pills counts) and defined as
follows: [0881] For insulin glargine/lixisenatide combination: any
dose corresponding to a lixisenatide daily dose greater than 40
.mu.g (i.e. >80 U for pen A, >120 U for pen B). [0882] For
insulin glargine: any dose administration which, in the
Investigator's opinion based on clinical judgment is considered
significantly greater than the prescribed dose of insulin. [0883]
An overdose with OADs (e.g. metformin) is defined as at least twice
of the intended dose within the intended/planned therapeutic
interval.
[0884] The circumstances of the overdose (ie, accidental or
intentional) should be clearly specified in the verbatim and
symptoms, if any, entered on separate AE forms.
[0885] Note:
[0886] Asymptomatic overdose with IMP does not need immediate
notification: the definition is the same as described above.
Asymptomatic overdose is to be reported in the standard AE page in
the e-CRF.
9.4.1.4 Other AEs Requiring Specific Monitoring and Reporting on
Specific e-CRFs
[0887] The following AEs require specific monitoring and should be
reported on the specific e-CRF completion. These AEs will only
qualify for expedited reporting when Serious (fulfilling SAE
criteria). [0888] Suspected allergic reactions (please refer to
Section 9.6.3), [0889] Monitoring of patients with increased
pancreatic enzymes>2 ULN/suspected pancreatitis (please refer to
Section 9.6.4), [0890] Major cardiovascular events (please refer to
Section 9.6.5), [0891] Monitoring of patients with increased
calcitonin 2:20 pg/mL (please refer to Section 9.6.6).
9.4.2 General Guidelines for Reporting Adverse Events
[0891] [0892] All AEs, regardless of seriousness or relationship to
IMP/NIMP, spanning from the signature of the informed consent form
until the end of the study as defined by the protocol for that
patient, are to be recorded on the corresponding page(s) or
screen(s) of the e-CRF. [0893] Whenever possible, diagnosis or
single syndrome should be reported instead of symptoms. The
Investigator should specify the date of onset, intensity, action
taken with respect to IMP, corrective treatment/therapy given,
additional investigations performed, outcome, and his/her opinion
as to whether there is a reasonable possibility that the AE was
caused by the IMP or NIMP or by the study procedure(s). [0894] For
the IMP (lixisenatide/insulin glargine combination) the causal
relationship assessment is for the combined product. [0895] The
Investigator should take appropriate measures to follow all AEs
until clinical recovery is complete and laboratory results have
returned to normal, or until progression has been stabilized, or
until death, in order to ensure the safety of the patients. This
may imply that observations will continue beyond the last planned
visit per protocol, and that additional investigations may be
requested by the monitoring team up to as noticed by the Sponsor.
[0896] When treatment is prematurely discontinued, the patients
observations will continue until the end of the study as defined by
the protocol for that patient. [0897] Laboratory, vital signs or
ECG abnormalities are to be recorded as AEs only if: [0898]
Symptomatic and/or [0899] Requiring either corrective treatment or
consultation, and/or [0900] Leading to IMP discontinuation or
modification of dosing, and/or [0901] Fulfilling a seriousness
criterion, and/or [0902] Defined as an AESI.
9.4.3 Instructions for Reporting Serious Adverse Events
[0903] In the case of occurrence of a SAE, the Investigator must
immediately: [0904] ENTER (within 24 hours) the information related
to the SAE in the appropriate screens of the e-CRF; the system will
automatically send the notification to the Monitoring Team after
approval of the Investigator within the e-CRF or after a standard
delay. [0905] SEND (preferably by fax or e-mail) the photocopy of
all examinations carried out and the dates on which these
examinations were performed, to the representative of the
Monitoring Team whose name, fax number and email address appear on
the Clinical Trial Protocol. Care should be taken to ensure that
the patient's identity is protected and the patient's identifiers
in the Clinical Trial are properly mentioned on any copy of source
document provided to the Sponsor. For laboratory results, include
the laboratory normal ranges. [0906] All further data updates
should be recorded in the e-CRF as appropriate, and further
documentation as well as additional information (for Lab data,
concomitant Medication, patient status . . . ) should be sent (by
fax or e-mail) to the Monitoring Team within 24 hours of knowledge.
In addition, any effort should be made to further document each
Serious AE that is fatal or life threatening within the week (7
days) following initial notification. [0907] A back-up plan is
available and should be used (using paper CRF process) when
thee-CRF system does not work (please see Appendix C).
[0908] Any SAE brought to the attention of the Investigator at any
time after the end of the study for the patient and considered by
him/her to be caused by the IMP with a reasonable possibility,
should be reported to the monitoring team.
9.4.4 Guidelines for Reporting Adverse Events of Special
Interest
[0909] For AES is, the Sponsor must be informed immediately (ie,
within 24 hours), as per SAE notification guidelines described in
Section 9.4.3, even if not fulfilling a seriousness criterion,
using the corresponding pages of the CRF (to be sent) or screens in
the e-CRF.
[0910] Instructions for AE reporting are summarized in Table 3.
9.4.5 Guidelines for Management of Specific Laboratory
Abnormalities
[0911] Decision trees for the management of certain laboratory
abnormalities by Sanofi are provided in Appendix B.
[0912] The following laboratory abnormalities should be monitored,
documented, and managed according to the related flow chart in
protocol Appendix B. [0913] Neutropenia [0914] Thrombocytopenia
[0915] Increase in ALT [0916] Acute renal failure [0917] Suspicion
of rhabdomyolysis
TABLE-US-00006 [0917] TABLE 3 Summary of Adverse Event Reporting
Instruction Case Report Form Completion Safety Comple- Other Event
Reporting Specific Events in AE mentary Specific Category Timeframe
This Category form Form Forms Adverse Routine Any AE that is no Yes
No No Event SAE or AESI (non-SAE, non-AESI) Serious Expedited Any
AE meeting Yes Yes No Adverse (within 24 seriousness Event hours)
criterion per (non-AESI Section 9.4.1.2 or AESI) Adverse Expedited
Pregnancy Yes Yes No Event (within 24 of female of Special hours)
patient/subject Interest Pregnancy (non-SAE) of female partner of
male patient/subject Symptomatic Yes Yes No overdose with IMP/NIMP*
Increase in ALT Yes No Yes AEs Routine Suspected Yes No Yes
requiring allergic specific reactions monitoring Increased Yes No
Yes (non-SAE) amylase/ lipase > 2 ULN Major cardio- Yes No Yes
vascular events Increased Yes No Yes calcitonin .gtoreq. 20 pg/mL
Laboratory, Routine Neutropenia Yes No No vital sign, or
Thrombocytopenia Yes No No ECG Acute renal Yes No No abnormality,
insufficiency asymptomatic Suspicion of Yes No No overdose
rhabdomyolysis recorded as Others (e.g. Yes No Yes/No AE (non-
leading to IMP SAE, non- discontinuation) AESI) Footnote:
Hypoglycemia will be reported on the dedicated hypoglycemia event
page. *Asymptomatic overdose is reported in the AE form and does
not require expedited reporting.
9.5 Obligations of the Sponsor
[0918] During the course of the study, the Sponsor will report in
an expedited manner: [0919] All SAEs that are both unexpected and
at least reasonably related to the IMP (SUSAR), to the regulatory
authorities, IECs/IRBs as appropriate and to the Investigators.
[0920] All SAEs that are expected and at least reasonably related
to the IMPs to the regulatory authorities, according to local
regulations.
[0921] Any other AE not listed as an expected event in the
lixiseantide/insulin glargine combination product Investigator's
Brochure (IB) will be considered as an unexpected event.
[0922] In this study, some AEs considered related to the underlying
condition (e.g. blood glucose increased) will not be considered
unexpected as given in the Investigator's Brochure.
[0923] The Sponsor will report all safety observations made during
the conduct of the trial in the clinical study report (CSR).
9.6 Safety Instructions
[0924] The study-specific safety instructions are given in this
Section.
9.6.1 Symptomatic Hypoglycemia
[0925] Symptomatic hypoglycemia events will be categorized as
follows:
Severe Symptomatic Hypoglycemia
[0926] Severe symptomatic hypoglycemia is an event requiring
assistance of another person to actively administer carbohydrate,
glucagon, or other resuscitative actions. These episodes may be
associated with sufficient neuroglycopenia to induce seizure,
unconsciousness or coma. Plasma glucose measurements may not be
available during such an event, but neurological recovery
attributable to the restoration of plasma glucose to normal is
considered sufficient evidence that the event was induced by a low
plasma glucose concentration.
[0927] The definition of severe symptomatic hypoglycemia includes
all episodes in which neurological impairment was severe enough to
prevent self-treatment and which were thus thought to place
patients at risk for injury to themselves or others.
[0928] Note that "requires assistance" means that the patient could
not help himself or herself. Assisting a patient out of kindness,
when assistance is not required, should not be considered a
"requires assistance" incident.
[0929] Severe symptomatic hypoglycemia will be qualified as an SAE
only if it fulfills SAE criteria. All events of seizure,
unconsciousness or coma must be reported as SAEs.
Documented Symptomatic Hypoglycemia
[0930] Documented symptomatic hypoglycemia is an event during which
typical symptoms of hypoglycemia are accompanied by a measured
plasma glucose concentration of 70 mg/dL (3.9 mmol/L). In addition,
hypoglycemia episodes with a plasma glucose of <60 mg/dL (3.3
mmol/L) will be analyzed.
[0931] Clinical symptoms that are considered to result from a
hypoglycemic episode can include (but not necessarily limited to):
increased sweating, nervousness, asthenia, tremor, dizziness,
increased appetite, palpitations, headache, sleep disorder,
confusion, seizures, unconsciousness, and coma.
Probable Symptomatic Hypoglycemia
[0932] Probable symptomatic hypoglycemia is an event during which
symptoms of hypoglycemia are not accompanied by a plasma glucose
determination, but was presumably caused by a plasma glucose
concentration less than or equal to 70 mg/dL (3.9 mmol/L); symptoms
treated with oral carbohydrate without a test of plasma
glucose.
[0933] Patients will be instructed to measure finger stick plasma
glucose levels prior to the administration of carbohydrates
whenever symptomatic hypoglycemia is suspected, unless safety
considerations necessitate immediate glucose rescue prior to
confirmation, and then a glucose measurement should be performed as
soon as safe, with appropriate diary documentation. Details on
hypoglycemia episodes will be captured in the patient diaries, and
patients will contact the sites as soon as possible following
severe events to review the details and decide on any necessary
measures to be taken.
[0934] Symptomatic hypoglycemia episodes will be documented on the
dedicated hypoglycemia event page in the e-CRF. Symptomatic
hypoglycemia events fulfilling the criteria of a SAE will also be
documented on AE and SAE complementary forms form in the e-CRF.
9.6.2 Local Tolerability at Injection Site
[0935] In case the investigator or the patient recognizes any signs
of local intolerability at injection site this should be recorded
on the standard AE page in the e-CRF.
9.6.3 Allergic or Allergic-Like Reaction
[0936] In case a patient experiences an allergic reaction or an
allergic-like reaction this has to be reported as an adverse event
and recorded in the e-CRF on the specific AE form for suspected
allergic event. Additional information is collected on specific
allergic reaction complementary form. Allergic reaction or possible
allergic reaction will be adjudicated by the ARAC (Section
5.4.2).
[0937] Virtually all symptoms listed on the allergic reaction
complementary form are possible adverse reactions that may be
allergic in nature and may need to be addressed after medical
judgment, excluding another etiology than allergy.
[0938] Sometimes transient injection site reactions, irritant in
nature may occur requiring no intervention and are of dubious
significance. These reactions would not be considered to be
allergic reactions. Adverse events that are obviously not of
allergic origin (e.g. local injection site reactions) should not be
recorded on the Allergic Reaction Complementary Form.
9.6.4 Monitoring of Patients with Increased Lipase and/or
Amylase>2 ULN
[0939] Potential safety signals for acute pancreatitis had been
identified in the post-marketing experience of other GLP-1 receptor
agonists. Therefore, patients enrolled in this study should be
followed for any suspected pancreatitis, e.g. with symptoms and/or
signs of acute abdominal distress or abnormal levels of pancreatic
enzymes. Serum amylase and lipase concentrations are monitored
routinely at screening, baseline and periodically during the study
treatment period.
[0940] In the presence of clinical signs and/or symptoms evocative
of pancreatitis, eg, persistent abdominal pain, which can radiate
to the back, often with characteristic positional features, with
possible occurrence of nausea, vomiting, fever and leucocytosis,
further measurement of amylase and lipase should be performed. The
clinical signs and/or symptoms should be documented in the source
data.
(1) Elevation of Amylase and/or Lipase>2 ULN without Clinical
Signs and/or Symptoms
[0941] In any case where amylase and/or lipase are >2 ULN, a
retest (centrally assessed as far as possible) must be performed as
follows: [0942] If value(s) is/are >2-3 ULN: retest within 7
days, [0943] If value(s) is/are >3 ULN: retest within 48 hours,
[0944] If the value(s) remain(s)>2 ULN upon retesting: amylase
and/or lipase levels should be retested weekly until values are
<2 ULN.
[0945] In case a retest is >2 ULN a gastroenterological
evaluation and imaging (ultrasound and/or CT or MRI with contrast,
as appropriate) must be pelformed. Please document in the source
data the absence of clinical signs and/or symptoms (if clinical
signs and/or symptoms develop, please see (2) below).
[0946] Best clinical judgment is to be used when interpreting
elevated serum amylase and lipase levels in asymptomatic patients.
Temporary discontinuation of the IMP may be considered in these
cases if deemed necessary by the Investigator.
(2) Elevation of Amylase and/or Lipase>2 ULN with Clinical Signs
and/or Symptoms
[0947] In the presence of clinical signs and/or symptoms evocative
of pancreatitis (as described above) associated with elevated
amylase and/or lipase, treatment with the IMP should be promptly
and at least temporarily discontinued pending further clinical
evaluation and diagnosis confirmation.
[0948] Clinical signs and/or symptoms are to be documented in the
source data. A laboratory determination of amylase and lipase has
to be obtained at the time of the event and again within 48 hours
or earlier as clinically indicated. If the value(s) remain(s)>2
ULN, then amylase and/or lipase levels should be retested as
described in (1) above, or more often if clinically indicated.
[0949] A gastroenterologic evaluation and imaging (ultrasound
and/or CT or MRI with contrast, as appropriate) must be performed.
If a diagnosis of pancreatitis is confi1 med, IMP should not be
restarted and should be permanently discontinued.
[0950] In both cases as described above under (1) and (2), all
laboratory or clinical documentations are to be collected. If the
retest confirms lipase and/or amylase values are >2 ULN, the
event must be reported in the eCRF on the specific AE form for
"Increased Lipase and/or Amylase>2 ULN" and the specific forms,
using the appropriate verbatim: eg, "increased amylase and/or
lipase" in case of isolated enzyme elevation, "suspected
pancreatitis" in the presence of clinical signs evocative of
pancreatitis if the diagnosis is suspected but cannot be confirmed
or excluded, and "pancreatitis" if the diagnosis has been
confirmed.
[0951] The PSAC will review selected pancreatic events, including
pancreatitis, pancreatic neoplasms and abnormal levels of amylase
or lipase.
9.6.5 Major Cardiovascular Events
[0952] In case a patient experiences a major cardiovascular event,
the investigator, in addition to adverse event reporting on
specific AE forms for cardiovascular events, has to collect more
detailed information on specific complementary forms. Major
cardiovascular events will be adjudicated by the CAC in a blinded
manner at the latest before the database lock. Please also refer to
Section 5.4.3.
9.6.6 Management of Patients with Increased Calcitonin Values
[0953] During the course of the study, if calcitonin value is found
2:20 pg/mL (5.9 pmol/L): [0954] A retest should be performed by the
central laboratory within 7 days. In addition, blood should be
collected and sent to the central laboratory for measurement of:
calcium, phosphorus, gastrin, Thyroid Stimulating Hormone (TSH),
and anti-thyroid peroxidase (anti-TPO) antibodies. [0955] The
clinical and laboratory documentations listed below are to be
collected and recorded in source documents as soon as possible:
[0956] Potential false positive circumstances: smoking status,
proton-pump inhibitor treatments (eg, omeprazole), autoimmune
thyroid diseases (Hashimoto's thyroiditis or Grave's disease),
differentiated thyroid cancer, hypercalcemia, hypergastrinemia,
chronic renal insufficiency (not on dialysis), other
neuro-endocrine tumors (lung small cell cancer, intestinal
carcinoid), acute pulmonary inflammatory conditions, or sepsis;
[0957] Specific personal and/or familial medical history in
relation to thyroid or other endocrine diseases; [0958] Specific
physical examination (neck, thyroid gland).
[0959] If the retest confirms that the calcitonin value is 20
pg/mL: [0960] The event must be reported in the e-CRF on the
specific AE form and specific complementary form for "increased
calcitonin 20 pg/mL" with all appropriate clinical and laboratory
documentation. [0961] An ultrasound scan of the thyroid should be
performed and the patient may be referred to a thyroid specialist
if judged necessary. [0962] The patient should continue to be
followed according to protocol schedule (including planned
calcitonin measurements). The specific AE form "increased
calcitonin 20 pg/mL (5.9 pmol/L)" should be updated with any new
information collected during the follow up. [0963] If a calcitonin
value 50 pg/mL (14.75 pmol/L) is found at any time during further
follow up, the patient should be permanently discontinued from IMP
(see Section 9.6.6) and referred to a specialist. As far as
possible, blood should be collected 1 to 2 weeks after IMP
discontinuation and sent to the central laboratory for calcitonin
measurement. [0964] If at any time during follow-up a calcitonin
value 20 pg/mL increases by 20% or more between 2 assessments
(while remaining below 50 pg/mL), a repeated measurement should be
performed earlier than scheduled in the protocol, ie, 1 month
later. Once results are available, discussion with Sponsor should
be initiated without delay for further guidance.
9.6.7 Monitoring of Renal Function in Case of Prolonged and Severe
Nausea and Vomiting
[0965] In case of prolonged or severe nausea and vomiting, if
clinically indicated, serum creatinine measurement has to be
centrally performed. If there is an acute increase of serum
creatinine, metformin (if taken) has to be discontinued until
resolution of renal dysfunction.
9.6.8 Follow-Up of Laboratory
[0966] abnormalities
[0967] Decision trees for the management of certain laboratory
abnormalities are provided in Appendix B (See FIG. 17 and FIG.
18).
9.7 Adverse Events Monitoring
[0968] All events will be managed and reported in compliance with
all applicable regulations, and included in the final clinical
study report.
10 STATISTICAL CONSIDERATIONS
10.1 Determination of Sample Size
[0969] The sample size calculations are based on the primary
efficacy variable change in HbA1c from baseline to Week 30, with
the following assumptions: [0970] A common standard deviation of
1.1%, [0971] A 0.4% mean difference between insulin
glargine/lixisenatide fixed ratio combination and insulin glargine
in change in HbA1c from baseline to Week 30, [0972] A t-test at a
2-sided 5% significance level with at least 95% power.
[0973] Based on the above assumptions, 350 patients per arm are
needed for this study.
[0974] Calculations were made using nQuery Advisor 7.0.
10.2 Disposition of Patients
[0975] The total number of patients for each of the following
categories will be presented in the CSR: [0976] Screened patients:
patients who have signed the informed consent, [0977] Run-in
patients: patients who had a run-in record in IVRS/IWRS database,
[0978] Randomized patients: patients with a treatment kit number
allocated and recorded in IVRS/IWRS database, and regardless of
whether the treatment kit was used or not. [0979] The safety
population (ie, randomized and treated patients), [0980] The
modified intent-to-treat (mITT) population (as defined in Section
10.3.1.1 and analyzed as randomized), [0981] The pharmacokinetic
(PK) population (as defined in Section 10.3.3), [0982] The
randomization strata [HbA1c at Visit 5 (<8%, 2:8%) and metformin
use at screening (Yes, No)] assigned by IVRS/IWRS will be
summarized. The discrepancy between the strata assigned by
IVRS/IWRS and the information reported on electronic Case Report
Form (eCRF) will be listed for all randomized patients, [0983]
Patients who have completed the 30-week treatment period, [0984]
Patients who discontinued the IMP during the 30-week treatment
period, and the reasons for treatment discontinuation.
[0985] For all categories of patients except screened and run-in
patients, percentages will be calculated using the number of
randomized patients as denominator for each treatment group.
[0986] A list of patients prematurely discontinued from the
treatment, along with reasons for discontinuation, will be
provided.
[0987] Patients treated but not randomized, patients randomized but
not treated and patients randomized but not treated as randomized
will be identified and described in separate listings. Only the
patients of the third category (randomized and not treated as
randomized) will be part of efficacy and safety analyses.
[0988] For any patient randomized more than once, only the data
associated with the first randomization will be used in any
analysis population. The safety experience associated with any
later randomization will be assessed separately.
[0989] The safety experience of patients treated and not randomized
will be reported separately, and these patients will not be in the
safety population.
10.3 Analysis Populations
10.3.1 Efficacy Populations
[0990] Efficacy analyses will be based on the treatment arm
allocated by the IVRS/IWRS according to the randomization schedule
at randomization visit (as randomized), irrespective of the
treatment arm actually received.
10.3.1.1 Modified Intent-to-Treat Population
[0991] Efficacy analyses will be based on the modified
intent-to-treat (mITT) population, defined as all randomized
patients who receive at least one dose of open-label IMP and have
both a baseline assessment and at least one post-baseline
assessment of any primary or secondary efficacy variables,
irrespective of compliance with the study protocol and procedures.
Patients will be analyzed for efficacy analyses according to the
treatment group to which they are randomized.
10.3.2 Safety Population
[0992] Safety analyses will be based on the safety population,
defined as all randomized patients who receive at least one dose of
open-label IMP (regardless of the amount of treatment
administered). Patients will be analyzed for safety analyses
according to the treatment actually received.
[0993] In addition: [0994] Nonrandomized but treated patients will
not be part of the safety population, but their safety data will be
presented separately. [0995] Randomized patients for whom it is
unclear whether they took the study medication will be included in
the safety population as randomized. [0996] When a patient is
exposed to both insulin glargine/lixisenatide fixed ratio
combination and insulin glargine, the patient will be analyzed in
the treatment group (insulin glargine/lixisenatide fixed ratio
combination or insulin glargine) in which he/she is treated longer.
[0997] Patients will be excluded from the safety population only if
there is documented evidence (ie, all study dates recorded as no
medication taken) that patients have not taken the study
medication.
10.3.3 Pharmacokinetic Population
[0998] For pharmacokinetic (PK) analyses, the PK population is
defined as all randomized and treated patients who contribute with
at least one valid plasma analysis of lixisenatide.
10.4 Statistical Methods
[0999] Continuous data will be summarized by treatment group using
the number of observations available (N), mean, standard deviation
(SD), minimum, median, and maximum.
[1000] Categorical data will be summarized by treatment group
`using count and percentage.
[1001] In general, descriptive statistics of quantitative efficacy
and safety parameters (result and change from baseline) by
scheduled visits will be provided on observed cases (OC), i.e.,
inclusion of only patients having non-missing assessments at a
specific visit.
10.4.1 Demographic and Baseline Characteristics
[1002] The baseline value is defined as the last available value
before the first injection of open-label Investigational Medicinal
Product (IMP). Derived parameters will be computed by the
sponsor.
[1003] Demographic characteristics to be summarized are: [1004] Age
(years) derived as: (Date of informed consent-Date of
birth)/365.25, [1005] Age categories (<50, .gtoreq.20 to <65,
.gtoreq.65 to <75, .gtoreq.75 years of age), Gender (Male,
Female), [1006] Race (Caucasian/White, Black, Asian/Oriental,
Other), [1007] Ethnicity (Hispanic, Not Hispanic), [1008] HbA1c (%)
at Visit 5 (Week -1), [1009] Randomization strata of HbA1c (<8,
.gtoreq.8%) at Visit 5 (Week -1), [1010] Randomization strata of
metformin use (Yes, No) at screening, [1011] Baseline BMI
(kg/m.sup.2) derived as: (Weight in kg)/(Height in meters)2, [1012]
Baseline BMI categories (<30, .gtoreq.30 kg/m.sup.2) [1013]
Country
[1014] Diabetes history includes [1015] Duration of diabetes
(years) derived as: (Date of informed consent-Date of diagnosis of
diabetes+1)/365.25, [1016] Age at onset of diabetes (years) derived
as: (Date of diagnosis of diabetes-Date of birth+1)/365.25, [1017]
Duration of basal insulin treatment (years) derived as: (Date of
informed consent-Date of first dose of basal insulin+1)/365.25,
[1018] Averaged daily dose of basal insulin at Visit 2 (Week -6)
and Averaged daily dose of insulin glargine at randomization Visit
6 (Week 0), [1019] Averaged daily dose of basal insulin within the
3 days immediately before screening at Visit 2 (Week -6) and
Averaged daily dose of insulin glargine within the 3 days
immediately before randomization at Visit 6, [1020] Percentage of
patients who used metformin at screening, [1021] Duration of
metformin treatment (years) (for patients who used metformin at
screening) derived as: (Date of informed consent-Date of first dose
of metformin+1)/365.25, [1022] Daily dose of metformin (mg) at
baseline, [1023] Categorized daily dose of metformin at baseline
(<1500, .gtoreq.1500 to <2500, .gtoreq.2500 to <3000,
.gtoreq.3000 mg), [1024] Percent of patients with number of OAD use
at screening (no OAD use, one OAD use, two OADs use), [1025]
Percent of patients with OAD use by class (i.e. metformin,
sulfonylurea, glinide, dipeptidylpeptidase4 inhibitor or SGLT-2
inhibitor alone, or in combination of any two of them), [1026]
Duration of first OAD (years) (for patients who used OAD at
screening) derived as: (Date of informed consent-Date of first dose
of OAD+1)/365.25, [1027] Duration of second OAD (years) (for
patients who used OAD at screening) derived as: (Date of informed
consent-Date of first dose of OAD+1)/365.25, [1028] Prior use of
GLP-1 receptor agonist (Yes, No), [1029] Baseline diabetic
microvascular complications (Yes, No) (ie, diabetic retinopathy,
diabetic sensory or motor neuropathy, diabetic autonomic
neuropathy, and diabetic nephropathy including the most recent
event categories). [1030] Baseline urine albumin/creatinine ratio
categories (<30 pg/mg [Normal], .gtoreq.30 to <300 [1031]
.mu.g/mg [Microalbuminuria], and 200 [Macroalbuminuria]), [1032]
Calculated creatinine clearance at screening (ml/min), [1033]
Calculated creatinine clearance categories at screening (<30
ml/min [Severe renal impairment], .gtoreq.30 to <50 ml/min
[Moderate renal impairment], .gtoreq.50 to .ltoreq.80 ml/min [Mild
renal impairment], and >80 ml/min [No renal impairment]).
[1034] The baseline efficacy variables include: [1035] HbA1c,
[1036] During standardized meal test: [1037] 2-hour postprandial
plasma glucose (PPG) and glucose excursion, [1038] 30-minute and
1-hour PPG and the corresponding glucose excursion. Note:
30-minute, 1-hour or 2-hour plasma glucose excursion=30-minute,
1-hour or 2-hour postprandial value-value obtained 30 minutes prior
to the start of meal and before IMP administration if IMP is
injected before breakfast) [1039] 7-point (average) Self-Monitored
Plasma Glucose, [1040] Body weight. [1041] Fasting plasma glucose
(by central laboratory),
[1042] Medical history and medical findings include: [1043]
Physical examination, [1044] Medical or surgical history, [1045]
Medical history of cardiovascular and cerebrovascular events,
[1046] Medical history of allergies, [1047] Subject family allergy
history, [1048] Alcohol habits within the last 12 months, [1049]
Smoking habits.
[1050] Medical and surgical history will be coded using the version
of Medical Dictionary for Regulatory Activities (MedDRA) currently
in effect at sanofi at the time of database lock.
[1051] No statistical test will be performed for the between-group
difference on demographic and baseline characteristics (including
medical history and baseline efficacy data).
[1052] Demographic and baseline disease characteristics, baseline
efficacy variables and medical history and medical findings will be
summarized with appropriate descriptive statistics by treatment
group and overall. Pathologies associated with past medical or
surgical history will be summarized by primary SOC and HLT. These
summaries will be provided on randomized patients.
10.4.2 Prior and Concomitant Medications
[1053] All medications will be coded using the version of World
Health Organization-Drug Dictionary (WHO-DD) currently in effect at
sanofi at the time of database lock.
[1054] Medications will be classified into the following three
groups: [1055] Prior medications are those the patient took prior
to the first injection of open-label IMP. [1056] Concomitant
medications are those the patient continued or started on or after
the first injection of open-label IMP up to 3 days after the last
injection of IMP. [1057] Post-treatment medications during the
follow-up period are those the patient continued or started on or
after 4 days after the last injection of open-label IMP.
[1058] A given medication can be classified in several groups.
Medications will be summarized according to the WHO-DD dictionary,
considering the first digit of the ATC class (anatomic category)
and the first three digits of the ATC class (therapeutic category).
All ATC codes corresponding to a medication will be summarized,
patients will be counted once in each ATC categories (anatomic or
therapeutic) linked to the medication, therefore patients may be
counted several time for the same medication.
[1059] Summaries of prior, concomitant and post-treatment
medications will be presented on randomized patients for each
treatment group (and overall for the summary of prior medications),
using counts and percentages. No statistical test for the
between-group difference will be performed.
10.4.3 Extent of Study Treatment Exposure and Compliance
[1060] The extent of study treatment exposure and compliance will
be assessed and summarized by actual treatment received in the
safety population.
10.4.3.1 Extent of Investigational Medicinal Product Exposure
[1061] The extent of study treatment exposure will be assessed by
the duration of treatment exposure during the study.
[1062] The duration of treatment exposure will be the total number
of days of administration of the open-label investigational
medicinal product, regardless of unplanned intermittent
discontinuations. The duration of IMP exposure will be calculated
as: (Date of the last open-label IMP injection-Date of the first
open-label IMP injection)+
[1063] The number (%) of patients randomized and exposed to the
open-label IMP will be presented by specific time periods for each
treatment group in the safety population. The time periods of
interest are grouped as follows: [1064] 1 to 14 days, [1065] 15 to
28 days, [1066] 29 to 56 days, [1067] 57 to 84 days, [1068] 85 to
126 days, [1069] 127 to 168 days, [1070] 169 to 210 days, [1071]
>210 days.
[1072] Descriptive statistics of duration of treatment exposure
(number, mean, SD, minimum, median, and maximum) and cumulative
exposure in patient year will also be presented by treatment group
in the safety population.
10.4.3.2 Compliance
[1073] Overall treatment compliance is defined as the actual number
of days with any IMP injection compared to the planned number of
days with IMP injection during the open-label treatment period, up
to treatment discontinuation. It is calculated according to the
following formula:
Compliance rate ( % ) = [ Total number of days with at least one
IMP injection Planned number of days with IMP injection ] .times.
100. ##EQU00001##
[1074] Treatment compliance will be summarized by treatment group
using mean, SD, median, and range for the safety population. In
addition, the percentage of patients who have <60%, 60 to
<80%, 80 to 100%, and >100% compliance will be summarized by
treatment group.
10.4.4 Analyses of Efficacy Endpoints
[1075] Efficacy analyses will be performed on the mITT population
using efficacy assessment obtained during the on-treatment period
(Section 8.1 and Section 8.2.1), unless otherwise specified.
[1076] For a patient to be included in a change from baseline
analysis (endpoint-baseline) or a baseline adjusted analysis of an
endpoint, the patient must have both a baseline and a post-baseline
on-treatment measure for that endpoint.
10.4.4.1 Analysis of Primary Efficacy Endpoint(s)
[1077] The statistical test will be two-sided tests at a nominal 5%
significance level.
[1078] The primary endpoint, change in HbA1c from baseline to Week
30, will be analyzed using a mixed-effect model with repeated
measures (Mt\11RM), under the missing at random framework. The MMRM
model will include treatment group (insulin glargine/lixisenatide
fixed ratio combination or insulin glargine), randomization strata
of HbA1c (<8, 2:8%) at Visit 5 (Week -1), randomization strata
of metformin use (Yes, No) at screening, visit (Week 8, Week 12,
Week 24, and Week 30), treatment-by-visit interaction and country
as fixed effects, and baseline HbA1c value-by-visit interaction as
a covariate. The adjusted mean change in HbA1c from baseline to
Week 30 for each treatment group will be estimated in the framework
of this model, as well as the between-group difference and the 95%
CI for the adjusted mean.
[1079] The MMRM model will be implemented using SAS.RTM. (Version
9.2 or higher) MIXED procedure (PROC MIXED) with an unstructured
correlation matrix to model the within-patient errors. Parameters
will be estimated using the restricted maximum likelihood method
with the Newton-Raphson algorithm. Denominator degree of freedom
will be estimated using the Kenward-Roger approximation by fitting
values from post-randomization scheduled visits during the
on-treatment period.
[1080] Primary analysis will be performed using the mITT population
and including all scheduled HbA1c measurements collected during the
on-treatment period.
Sensitivity Analyses
[1081] The following sensitivity analyses will be performed for the
primary endpoint.
[1082] In order to assess the impact of rescue therapy, a
sensitivity analysis in a multilevel model with random slopes and
intercepts, will be performed using all HbA1c data collected until
the treatment cessation plus 14 days (including data collected
after the introduction of rescue therapy). A multilevel model with
random slopes and intercepts will be used to adjust for the effect
of rescue medication on the change from baseline in HbA1c. This
model will include treatment (insulin glargine/lixisenatide fixed
ratio combination or insulin glargine), randomization strata of
HbA1c (<8, .gtoreq.8%) at Visit 5 (Week -1), randomization
strata of metformin use (Yes, No) at screening, visit (Week 8, Week
12, Week 24, and Week 30), treatment-by visit interaction, country
as fixed-effect factors, and baseline HbA1c-by-visit interaction,
and the number of days spent on rescue medications as covariates.
The multilevel model will be implemented via PROC MIXED. Parameters
will be estimated using the restricted maximum likelihood method
with the Newton-Raphson algorithm. Denominator degrees of freedom
will be estimated using the Kenward-Reger approximation by fitting
values from all post-randomization visits in the on-treatment
period.
[1083] An analysis of covariance (ANCOVA) with the missing data
imputed by the Last Observation Carried Forward (LOCF) will be
performed on the primary efficacy variable. Each patients last
available post-baseline on-treatment HbA1c measurement (before the
rescue medication is taken in the event of rescue therapy) will be
modeled with treatment groups (insulin glargine/lixisenatide fixed
ratio combination or insulin glargine), randomization strata of
HbA1c (<8, .gtoreq.8%) at Visit 5 (Week -1), randomization
strata of metformin use (Yes, No) at screening, and country as
fixed effects and using the baseline HbA1c value as a covariate.
Adjusted mean estimates by treatment and the difference of these
estimates (insulin glargine/lixisenatide fixed ratio combination
versus insulin glargine) will be provided as well as 95% confidence
intervals (CI) of the differences and p-value.
[1084] A sensitivity analysis will also be conducted on the 30-week
completers in mITT population (ie, all mITT patients who completed
the 30-week open-label treatment period and did not start any
rescue therapy before the end of the 30 week treatment period)
using the observed Week 30 values and the same MMRM model as
described in the primary analysis above.
Assessment of Treatment Effect by Subgroup
[1085] Descriptive analyses will be performed on the primary
endpoint to summarize the treatment effects across subgroups
defined by the following baseline or screening factors: [1086]
Race, [1087] Ethnicity (Hispanic, Not Hispanic), [1088] Age group
(<50, .gtoreq.50 to <65, .gtoreq.65 years of age), [1089]
Gender, [1090] Baseline BMI level (<30, .gtoreq.30 kg/m.sup.2),
[1091] Baseline HbA1c (<8, .gtoreq.8%), [1092] Metformin use
(Yes, No) at screening, [1093] Country. [1094] Number of OAD use at
screening (no OAD use, one OAD use, two OADs use).
[1095] The treatment effects across the subgroups defined for each
of these factors will be estimated for the change from baseline to
Week 30 in HbA1c in the mITT population excluding the assessments
done after the introduction of a rescue medication, and using the
MMRM approach with treatment group (insulin glargine/lixisenatide
fixed ratio combination or insulin glargine), randomization strata
of HbA1c (<8, a %) at Visit 5 (Week -1), randomization strata of
metformin use (Yes, No) at screening, visit, subgroup factor,
treatment-by-visit, treatment-by-subgroup factor, visit-by-subgroup
factor, treatment-by-visit-by-subgroup factor, and country as fixed
effects and using baseline HbA1c value-by-visit interaction as a
covariate. The adjusted estimates of treatment mean differences
(insulin glargine/lixisenatide fixed ratio combination versus
insulin glargine alone and versus lixisenatide alone) with standard
errors and 95% confidence intervals will be provided as appropriate
across the subgroups.
[1096] In case that the subgroup factor is identical or similar to
a randomization strata factor (e.g. baseline HbA1c category or
metformin use), only the subgroup factor will be included in the
model in order to avoid collinearity issue in the analysis.
[1097] A similar MMRM model will also be used to estimate the
within-group treatment effect for the change from baseline to Week
30 in HbA1c for the following subgroups: [1098] Anti-lixisenatide
antibody status (positive, negative) at the end of 30-week
treatment, [1099] Anti-insulin glargine antibody status (positive,
negative) at the end of 30-week treatment, [1100] Anti-lixisenatide
antibody concentration at the end of 30-week treatment: <lower
limit of quantification (LLOQ), 2:LLOQ to 100, >100 nmol/L.
[1101] The adjusted means for each treatment group will be provided
across the subgroups as appropriate, as well as the associated
standard errors and 95% confidence intervals.
[1102] The change of HbA1c from baseline over time by visit will be
evaluated by descriptive statistics (mean, standard deviation,
median and ranges).
10.4.4.2. Analyses of Secondary Efficacy Endpoints
[1103] Descriptive statistics (number, mean, standard deviation,
median, minimum, and maximum) will be provided by treatment for all
continuous secondary variables at the scheduled visits.
[1104] Except for 30-minute, 1-hour, 2-hour PPG and glucose
excursion, all continuous secondary efficacy endpoints at Week 30
defined in Section 8.2.1 will be analyzed using the same MMRM
approach as described in Section 10.4.4.1 to compare insulin
glargine/lixisenatide fixed ratio combination with insulin
glargine. This model will include fixed effect terms including
treatment group (insulin glargine/lixisenatide fixed ratio
combination or insulin glargine), randomization strata of HbA1c
(<8, 2:8%) at Visit 5 (Week -1), randomization strata of
metformin use (Yes, No) at screening, scheduled visit,
treatment-by-visit interaction, and country, and the covariate
baseline value-by-visit interaction (except for insulin glargine
dose at week 30, for which the MMRM model will not be adjusted on
the baseline value). Means and adjusted means of each treatment
group will be provided, as well as adjusted mean and associated
two-sided 95% CI of the differences between treatment groups. The
statistical tests for between-group differences will be two-sided
at the alpha level of 0.05. The analyses include all scheduled
measurements collected during the on-treatment period.
[1105] Thirty-minute, 1-hour, 2-hour PPG and glucose excursion, for
which only one on-treatment assessment is scheduled, will be
analyzed using the similar ANCOVA with the missing data imputed by
LOCF as described in Section 10.4.4.1 to compare insulin
glargine/lixisenatide fixed ratio combination with insulin
glargine. This model will include fixed effect terms including
treatment groups, randomization strata of HbA1c (<8, 2:8%) at
Visit 5 (Week -1), randomization strata of metformin use (Yes, No)
at screening, and country, and a covariate using the corresponding
baseline value. Means and adjusted means of each treatment group
will be provided, as well as adjusted mean and associated two-sided
95% CI of the difference between treatment groups. In case of
discontinuation of study drug before Week 30, 30-minute, 1-hour,
2-hour PPG and glucose excursion will be assessed at the time of
discontinuation. The LOCF procedure will be used by taking this
last available post-baseline on-treatment measurement (before the
rescue medication is taken in the event of rescue therapy) as the
value at Week 30.
[1106] All categorical secondary efficacy endpoints defined in
Section 8.2.1 will be analyzed using a Cochran-Mantel-Haenszel
(CMH) method stratified on randomization strata of HbA1c (<8,
8%) at Visit 5 (Week -1) and randomization strata of metformin use
(Yes, No) at screening. The proportion in each treatment group will
be provided, as well as the difference of proportions between
groups with associated 2-sided 95% CI. For HbA1c responders at Week
30 (6.5%, <7% respectively), patients who had no assessments at
Week 30 during the on-treatment period will be treated as failures
(non-responders) in the analysis, including those who discontinue
study treatment before Week 30, start rescue medication before Week
30, or have no on-treatment assessments at all in mITT population.
For each categorical composite endpoint, a patient will be treated
as a responder only if the criterion is met for each component of
the composite endpoint.
10.4.4.3 Multiplicity Considerations (to be Determined)
[1107] To control the Type I error, a step-down testing procedure
will be applied.
[1108] For the primary variable (change from baseline to Week 30 in
HbA1c), no multiplicity adjustment is needed to control the Type I
error since only one comparison of insulin glargine/lixisenatide
fixed ratio combination versus insulin glargine will be
performed.
[1109] If the primary variable is statistically significant at the
5% level, a hierarchical testing procedure will be performed to
test the following secondary efficacy variables in the following
prioritized order. Testing will stop when an endpoint is found not
to be statistically significant at the 5% level: [1110] 1. Change
in 2-hour blood glucose excursion during the standardized meal test
from baseline to Week 30, [1111] 2. Change in body weight from
baseline to Week 30, [1112] 3. Change in the daily average of the
7-point SMPG from baseline to Week 30, [1113] 4. Percentage of
patients reaching HbA1c<7% with no body weight gain at week 30,
[1114] 5. Change in daily dose of insulin glargine from baseline to
Week 30, Multiplicity adjustment will not be performed on the
secondary efficacy variables that are not included in the above
list.
10.4.5 Analyses of Safety Data
[1115] The summary of safety results will be presented by treatment
group.
[1116] All safety analyses will be performed on the Safety
population as defined in Section 10.3.2 using the following common
rules:
[1117] The baseline value is defined generally as the last
available value before randomization.
[1118] The following definitions will be applied to laboratory
parameters and vital signs. [1119] The potentially clinically
significant abnormality (PCSA) values for clinical laboratory tests
and vital signs are defined as abnormal values considered medically
important by the Sponsors Global Pharmacovigilance and Epidemiology
department and in effect at the time of the final SAP approval.
PCSA criteria for parameters not cited in the protocol as safety
parameters will not be analyzed. [1120] PCSA criteria will
determine which patients had at least 1 PCSA during the
on-treatment period, taking into account all evaluations performed
during the on-treatment period, including unscheduled or repeated
evaluations. The number of all such patients will be the numerator
for the on-treatment PCSA percentage.
[1121] The "observation period" defined in Section 8.2.2 are
applicable for classification of AEs, determination of on-treatment
PCSA values and the last on-treatment value for the laboratory,
vital sign and ECG parameters.
10.4.5.1 Analyses of Symptomatic Hypoglycemia
[1122] The number (%) of patients and rate in patient years (2
types: the number of patients with events or the total number of
events per 100 patient-year) of each type of symptomatic
hypoglycemia (severe, documented and probable symptomatic
hypoglycemia) will be summarized by treatment group. The pattern of
symptomatic hypoglycemia occurrence over time will also be
assessed, as appropriate.
[1123] In addition to the threshold of less than or equal to 70
mg/dL (3.9 mmol/L) (please refer to Section 9.6.1 symptomatic
hypoglycemia episodes with a plasma glucose of <60 mg/dL (3.3
mmol/L) will be analyzed separately.
10.4.5.2 Analyses of Adverse Events
[1124] Pre-treatment AEs are AEs that developed or worsened or
became serious during the pre-treatment period.
[1125] Treatment-emergent AEs (TEAEs) are AEs that developed or
worsened (according to the investigators opinion) or became serious
during the on-treatment period.
[1126] Post-treatment AEs are AEs that developed or worsened or
became serious during the post-treatment period.
[1127] The primary focus of AE reporting in the CSR will be on
TEAEs. Pre- and post-treatment AEs will be described
separately.
All Adverse Events
[1128] Adverse event incidence tables will present by system organ
class (SOC) (sorted by internationally agreed order), high-level
group term (HLGT), high level term (HLT) and preferred term (PT)
sorted in alphabetical order for each treatment group, the number
(n) and percentage (%) of patients experiencing an AE. Multiple
occurrences of the same event in the same patient will be counted
only once in the tables within a treatment phase. The denominator
for computation of percentages is the safety population within each
treatment group.
[1129] Summaries of all TEAEs in each treatment group will include:
[1130] The overview of AEs, summarizing number (%) of patients with
any [1131] TEAE, [1132] serious TEAE, [1133] TEAE leading to death,
[1134] TEAE leading to permanent treatment discontinuation. [1135]
The number (n) and percentage (%) of patients with at least one
TEAE by primary SOC, HLGT, HLT and PT, [1136] Summary of TEAEs by
maximal severity (severe, moderate, mild), presented by primary SOC
and PT, [1137] Summary of TEAEs possibly related to open-label IMP,
presented by primary SOC, HLGT, HLT and PT.
[1138] A detailed listing of TEAE summaries will be provided in the
statistical analysis plan.
Death and Serious Adverse Events
[1139] Death and treatment-emergent SAEs will be summarized and
presented as number and percent of patients in each treatment
group.
[1140] The following deaths summaries will be generated: [1141]
Number (%) of patients who died by study period (TEAE, on-study)
summarized on the safety population by treatment received [1142]
Death in nonrandomized patients or randomized and not treated
patients [1143] TEAE leading to death (death as an outcome on the
AE e-CRF page as reported by the Investigator) by primary SOC,
HLGT, HLT and PT showing number (%) of patients sorted by
internationally agreed order of SOC and alphabetic order of HLGT,
HLT, and PT.
Adverse Events Leading to Permanent Treatment Discontinuation
[1144] TEAEs leading to permanent treatment discontinuation will be
summarized and presented as number and percent of patients in each
treatment group.
Local Tolerability at Injection Site
[1145] AEs related to local intolerability at the injection site
will be identified by searching the term "injection site" in either
the PTs coded from the investigator reported terms or the PTs coded
from the ARAC diagnosis terms. The number (%) of patients with
related events will be summarized by treatment group.
Allergic Reactions
[1146] The number (%) of patients with events adjudicated as
allergic reactions by ARAC and with events adjudicated by ARAC as
possibly related to the IMP will be summarized by treatment group.
All the allergic events reported by the investigators on the AE
form for suspected allergic event and its associated complementary
forms (confirmed or not confirmed by ARAC) will be listed.
Increased Pancreatic Enzymes>2 Times ULN
[1147] The number (%) of patients with events reported on the AE
form for increased lipase and/or amylase>2 times ULN and its
associated complementary forms will be summarized by PTs for each
treatment group.
Major Cardiovascular Events
[1148] Major cardiovascular events positively adjudicated and
confirmed by CAC will not be summarized in the CSR. All events
reported by the Investigators on the AE forms for cardiovascular
events and the associated complementary forms (confirmed or not
confirmed by CAC) will be listed along with the adjudication
outcome.
Increased Calcitonin Values
[1149] The number (%) of patients with events reported on the AE
form for increased calcitonin 220 pg/mL and its associated
complementary forms will be summarized by PTs for each treatment
group.
ALT Increase
[1150] The number (%) of patients with events reported on the AE
form for ALT increase and its associated complementary forms will
be summarized by PT for each treatment group.
10.4.5.3 Analyses of Laboratory Variables
[1151] The number and percentage of patients with PCSA at any
evaluation during the on-treatment period will be summarized for
each clinical laboratory test within each treatment group. The
summaries will include patients in the safety population who have
at least one laboratory test performed during the on-treatment
period and, when required by the definition of the abnormality,
with an available baseline value and available laboratory normal
ranges.
[1152] Descriptive statistics will be used to summarize the
laboratory results and the changes from baseline by visit and for
the last on-treatment value within each treatment group.
[1153] Shift tables and other tabular and graphical methods may be
used to present the results for laboratory tests of interest.
[1154] Listings will be provided with flags indicating the out of
laboratory range values as well as the PCSA values.
Drug-Induced Liver Injury
[1155] The liver function tests, namely AST, ALT, alkaline
phosphatase and total bilirubin are used to assess possible drug
induced liver toxicity. The proportion of patients with PCSA values
at any post baseline visit by baseline status will be displayed by
treatment group for each parameter. The proportion of patients with
PCSA values at any post baseline visit will also be displayed by
duration of exposure for each treatment group only if a tabulation
summary is necessary.
[1156] A listing will be provided of possible Hy's Law cases
identified by treatment group (eg, patients with any elevated
ALT>3.times.ULN, and associated with an increase in total
bilirubin 2:2.times.ULN) with liver-related TEAEs, ALT, AST, ALP,
total bilirubin and the following complementary parameters, if
available: Conjugated Bilirubin and Prothrombin Time/INR, creatine
phosphokinase, serum creatinine, complete blood count, Immunoglobin
M (IgM) antibodies to Hepatitis A virus, IgM antibodies to
Hepatitis B core antigen, antibodies to Hepatitis C Virus, and
Hepatitis C ribonucleic acid, IgM antibodies to Cytomegalovirus,
and IgM antibodies to Hepatitis E virus, Auto-antibodies:
anti-nuclear, anti-deoxyribonucleic acid, anti-smooth muscle,
Epstein-Barr virus, Herpes viruses and anti-liver/kidney
microsomes.
10.4.5.4 Analyses of Vital Sign Variables
[1157] The number and percentage of patients with PCSA at any
evaluation during the on-treatment period will be summarized for
each vital sign parameter within each treatment group. The
summaries will include patients in the safety population who have
at least one parameter to be analyzed during the on-treatment
period. When the PCSA definition involves the change from the
baseline value, patients need also to have a baseline value to be
included in the summaries.
[1158] Descriptive statistics will be used to summarize the results
and the changes from baseline by visit and for the last
on-treatment value within each treatment group.
[1159] Tabular and graphical methods may be used to present the
results for parameters of interest.
[1160] Listings will be provided with flags indicating the PCSA
values.
10.4.5.5 Analyses of 12 Lead ECG Status
[1161] A shift table will be provided to present the ECG
on-treatment status according to the baseline status within each
treatment group
10.4.5.6 Analyses of Anti-Drug Antibody Variables
[1162] Analyses of antibody variables will be performed on the
safety population (ie, in patients from both treatment groups for
anti-insulin glargine antibody; in patients from the insulin
glargine/lixisenatide fixed ratio combination group only for
anti-lixisenatide antibody).
[1163] The number and percentage of patients by antibody status
will be listed and summarized by treatment group and visit, as well
as the percentage of conversion from negative to positive status
from baseline to Week 30. For anti-insulin antibodies, the number
and percentage of patients with cross reactivity to human insulin
will also be summarized by treatment group and visit in
anti-insulin glargine positive patients.
[1164] Antibody levels (titer or concentration), as well as
respective percent changes from baseline for anti-insulin glargine
antibodies, will be listed and summarized by treatment group and
visit using descriptive statistics by N, geometric mean,
coefficient of variation, median, minimum and maximum.
10.4.6 Analyses of Pharmacokinetic Variables
[1165] Lixisenatide plasma concentrations (total and active) of
patients in the insulin glargine/lixisenatide fixed ratio
combination group will be listed and summarized by visit and time
window and by anti-lixisenatide antibody status in the PK
population, using descriptive statistics by N, geometric mean,
coefficient of variation, median, minimum and maximum.
[1166] Population PK modeling might be pursued for exploratory
purpose.
10.4.7 Analyses of Patient Reported Outcomes Variables
[1167] The analyses of TRIM-D, EQ-5D and IWQoL-Lite will be
performed on the mITT population.
[1168] The change in all computed PRO scores (global and for each
domain of the different questionnaires) from baseline to endpoint
will be analyzed using a similar MMRM model than the one of the
primary endpoint.
[1169] Descriptive statistics (mean, median, standard deviation and
range) for absolute values and for changes from baseline will be
presented by treatment group per visit for each score (global and
for each domain of each questionnaire) as well as for each
item.
[1170] Moreover, the responses of each EQ-5D item will be presented
by visit for each treatment group. The tables will contain
information on the frequency and proportion of the population
reporting level 1 (no problems), level 2 (some problems) and level
3 (extreme problems) per item, by treatment group and by visit.
[1171] The analyses of the patient-rated and physician-rated global
treatment effectiveness evaluation scales will be performed on the
mITT population. Descriptive statistics (mean, median, standard
deviation and range) for patient- and physician-rated global
evaluation scales will also be presented by treatment group at the
end of the study.
10.5 Interim Analysis
[1172] No formal interim analysis for efficacy is planned for this
study. The study will not be terminated early for excellent
efficacy.
[1173] An independent Data Monitoring Committee (DMC) will monitor
and assess the safety of patients from this trial through periodic
review of the accumulated safety data provided by an independent
statistical group. Related details are provided in separate
documents (DMC charter and DMC statistical analysis plan).
11 APPENDICES
TABLE-US-00007 [1174] APPENDIX A Calculation of
creatinine-clearance by Cockroft and Gault Creatinine Clearance
Calculation Name Decimal Formula Units Places Conventional: mL/min
0 Male: ((140-age) .times. (weight (kg))/((72 .times. serum
Creatinine (mg/dL)) Female: [(0.85 .times. (140-age) .times.
(weight (kg)]/[72 .times. serum Creatinine (mg/dL)] SI: mL/sec 2
Male: [(140-age) .times. (weight (kg))]/[72 .times. serum
Creatinine (.mu.mol/L) .times. 0.6786)] Female: [0.85
.times.(140-age) .times. (weight (kg))]/[(72 .times. serum
Creatinine (.mu.mol/L) .times. 0.6786)]
[1175] Appendix B: General Guidance for the follow-up of laboratory
abnormalities by Sanofi (See FIG. 17 and FIG. 18).
Note on Naeutropenia (FIG. 17):
[1176] The procedures described in the above flowchart are to be
discussed with the patient only in case the event occurs. If
applicable (according to local regulations), an additional consent
(e.g., for HIV testing) will only be obtained in the case the event
actually occurs. [1177] For individuals of African descent, the
relevant value of concern is <1000/mm3 Neutropenia are to be
recorded as AE only if they are: [1178] Symptomatic, and/or [1179]
Requiring either corrective treatment or consultation, and/or
[1180] Leading to IMP discontinuation or modification of dosing,
and/or [1181] Fulfilling a seriousness criterion [in that case, the
event (SAE) should be notified within 24 hours to the MT], and/or
[1182] Defined as an Adverse Event of Special Interest (AESI)
Note on Thrombocytopenia (FIG. 18):
[1183] The procedures described in the above flowchart are to be
discussed with the patient only in case the event occurs. If
applicable (according to local regulations), an additional consent
(e.g., for HIV testing) will only be obtained in the case the event
actually occurs. Thrombocytopenia are to be recorded as AE only if
they are: [1184] Symptomatic, and/or [1185] Requiring either
corrective treatment or consultation, and/or [1186] Leading to IMP
discontinuation or modification of dosing, and/or [1187] Fulfilling
a seriousness criterion [in that case, the event (SAE) should be
notified within 24 hours to the MT], and/or [1188] Defined as an
Adverse Event of Special Interest (AESI)
[1189] Note on FIG. 19: In addition, as soon as a seriousness
criterion is met, the event should be notified within 24 hours to
the monitoring team.
Notes on Acute Renal Failure (FIG. 20)
[1190] Acute renal failure is to be recorded as an AE only if it
is: [1191] Symptomatic, and/or [1192] Requiring either corrective
treatment or consultation, and/or [1193] Leading to IMP
discontinuation or modification of dosing, and/or [1194] Fulfilling
a seriousness criterion [in that case, the event (SAE) should be
notified within 24 hours to the MT], and/or [1195] Defined as an
Adverse Event of Special Interest (AESI)
Notes on Suspicion of Rhabdomyolysis (FIG. 21)
[1196] Suspicion of rhabdomyolysis is to be recorded as an AE only
if it is: [1197] Symptomatic, and/or [1198] Requiring either
corrective treatment or consultation, and/or [1199] Leading to IMP
discontinuation or modification of dosing, and/or [1200] Fulfilling
a seriousness criterion [in that case, the event (SAE) should be
notified within 24 hours to the MT], and/or [1201] Defined as an
Adverse Event of Special Interest (AESI)
[1202] Appendix C: Back-up Plan for SAE and other Investigator
Expedited Events reporting process when the e-CRF system fails (see
FIG. 22)
[1203] Appendix D: Treatment-Related Impact Measure for Diabetes
(TRIM-D) (see FIGS. 23, 24 and 25)
[1204] (For information only)
[1205] Appendix E: EuroQoL Five Dimension (EQ-5D) (see FIGS. 26 and
27)
[1206] (For information only)
[1207] Appendix F: Impact of Weight on Quality of Life-Lite
(IWQOL-Lite) (see FIGS. 28 and 29)
[1208] (For information only)
Example 2
[1209] A randomized, 30-week, active controlled, open label,
3-treatment arm, parallel-group multicenter study comparing the
efficacy and safety of insulin glargine/lixisenatide fixed ratio
combination to insulin glargine alone and to lixisenatide alone on
top of metformin in patients with Type 2 diabetes mellitus
(T2DM)
1 ABBREVIATIONS
[1210] AE: Adverse event [1211] ALT: Alanine aminotransferase
[1212] ANCOVA: Analysis of covariance [1213] ARAC Allergic Reaction
Assessment Committee [1214] BMI: Body mass index [1215] CI:
Confidence interval [1216] CMH: Cochran-Mantel-Haenszel [1217] FPG:
Fasting plasma glucose [1218] IMP: Investigational medicinal
product [1219] LS: Least squared [1220] mITT: Modified
Intent-To-Treat [1221] PPG: Postprandial plasma glucose [1222] PT:
Preferred term [1223] SAE: Serious adverse event [1224] SMPG:
Self-monitored plasma glucose [1225] SOC: System organ class [1226]
T2DM Type 2 diabetes mellitus [1227] TEAE: Treatment-emergent
adverse event
2 Synopsis
[1228] Title of the study: A randomized, 30-week,
active-controlled, open label, 3-treatment arm, parallel-group
multicenter study comparing the efficacy and safety of insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
alone and to lixisenatide alone on top of metformin in patients
with Type 2 diabetes mellitus (T2DM) Study center(s): Multicenter
(240 centers in 23 countries)
Publications (reference): NA Phase of development: Phase 3
Objectives:
Primary Objective:
[1229] To demonstrate the superiority of the insulin glargine
lixisenatide fixed ratio combination to lixisenatide in
glycosylated hemoglobin A1c (HbA1c) change from baseline to Week
30.
[1230] To demonstrate the non-inferiority of the insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
in HbA1c change from baseline to Week 30.
[1231] Secondary Objectives:
[1232] To assess the effects of the insulin glargine/lixisenatide
fixed ratio combination in comparison with insulin glargine and
lixisenatide alone over 30 weeks on: [1233] Percentage of patients
reaching HbA1c targets; [1234] Glycemic control in relation to a
meal as evaluated by glucose excursion and 2-hour postprandial
plasma glucose (PPG) [1235] during a standardized meal test; [1236]
Body weight; [1237] Fasting plasma glucose (FPG) [1238] 7-point
Self-Monitored Plasma Glucose profile [1239] Percentage of patients
reaching HbA1c targets with no body weight gain and/or documented
symptomatic hypoglycemia; [1240] Insulin glargine dose (in the
combination and insulin glargine groups). To assess the safety and
tolerability in each treatment group.
[1241] Methodology: This was an open-label, 2:2:1 randomized,
active-controlled, 3-group, 30-week treatment duration,
parallel-group multinational and multicenter study. Randomization
was stratified by values of HbA1c at visit 4 (<8%, 8%) and
second oral anti-diabetic (OAD) use at screening (Yes, No).
[1242] The study comprised 3 periods: (1) An up to 6-week screening
phase (including an up to 2-week screening phase and a 4-week
run-in phase where a sulfonylurea (SU), glinide, sodium glucose
co-transporter-2 (SGLT-2) inhibitor, or dipeptidyl peptidase-4
(DPP-4) inhibitor if previously taken were discontinued and
metformin treatment optimized up to a daily dose of at least 2000
mg or the maximal tolerated dose (1500 mg/day)); (2) a 30-week
open-label randomized treatment period; and (3) a 3-day
post-treatment safety follow-up period.
[1243] Number of patients: Planned: 1125 [1244] Randomized: 1170
[1245] Treated: 1169
[1246] Evaluated: Efficacy: 1167 [1247] Safety: 1169
[1248] Diagnosis and criteria for inclusion: Inclusion criteria:
Patients with type 2 diabetes mellitus
[1249] (T2DM) diagnosed for at least 1 year before the screening
visit, treated for at least 3 months prior to Visit 1 with
metformin alone or metformin and a second oral anti-diabetic
treatment that could be a SU, a glinide, a SGLT-2 inhibitor, or a
DPP-4 inhibitor, and who were not adequately controlled with this
treatment. Key exclusion criteria at screening: HbA1c<7.5% or
>10.0% for patients previously treated with metformin alone;
HbA1c<7.0% or >9.0% for patients previously treated with
metformin and a second oral anti-diabetic treatment; Body Mass
Index (BMI).ltoreq.20 or >40 kg/m2.
Study Treatments
[1250] Investigational medicinal product(s) (IMPs): Tested drug:
Insulin glargine/lixisenatide fixed ratio combination; Controlled
drugs: Insulin glargine (Lantus.RTM.) and lixisenatide
Formulation:
Insulin Glargine/Lixisenatide Fixed Ratio Combination
[1251] Insulin glargine/lixisenatide fixed ratio combination
(hereafter referred to as fixed ratio combination) was supplied as
a sterile aqueous solution in a pre-filled disposable SoloStar.RTM.
pen-injector.
[1252] Two pens (A and B) with different fixed ratios were
available to allow insulin glargine titration over a range of 10 to
60 U/day while limiting the lixisenatide dose to a maximum of 20
.mu.g/day: [1253] Pen A contained 100 U/mL of insulin glargine and
50 pg/mL of lixisenatide in ratio of 2:1 (2 units of insulin
glargine per 1 .mu.g lixisenatide). Doses could be set from 10 to
40 units in steps of 1 unit, allowing administration of daily
combination doses between 10 U/5 .mu.g and 40 U/20 .mu.g. [1254]
Pen B contained 100 U/mL insulin glargine and 33 pg/mL lixisenatide
in a ratio of 3:1. Doses could be set from 30 to 60 units in steps
of 1 unit, allowing administration of daily combination doses
between 30 U/10 .mu.g and 60 U/20 .mu.g.
[1255] The maximum daily dose was 60 units (60 units insulin
glargine and 20 .mu.g lixisenatide).
Insulin Glargine
[1256] Insulin glargine was suppled as a sterile aqueous solution
in a pre-filled disposable Lantus.RTM. SoloStar.RTM. pen-injector
(100 U/mL).
[1257] Doses could be set from 1 to 80 units in steps of 1 unit.
However, in this study the maximum insulin glargine daily dose
allowed was 60 U.
Lixisenatide
[1258] Lixisenatide was supplied as a disposable pre-filled pen
(lixisenatide pen): [1259] 10 .mu.g initiation dose: disposable
pen-injector device containing 3 mL of a sterile aqueous solution
with 150 .mu.g of the active ingredient (50 .mu.g/mL) [1260] 20
.mu.g maintenance dose: disposable pen-injector device containing 3
mL of a sterile aqueous solution with 300 .mu.g of the active
ingredient (100 .mu.g/mL)
[1261] Route(s) of administration: Subcutaneous injection for all
IMPs. The fixed ratio combination was self-administered with a
pre-filled disposable SoloStar.RTM. pen-injector. Insulin glargine
was self-administered with a pre-filled disposable Lantus.RTM.
SoloStar.RTM. pen-injector. Lixisenatide was self-administered with
a pre-filled disposable pen (lixisenatide pen).
Dose Regimen:
Fixed Ratio Combination
[1262] The fixed ratio combination was self-administered once daily
in the morning, in the hour (0 to 60 minutes) before breakfast.
Treatment was initiated with Pen A at a daily dose of 10 U of
insulin glargine/5 .mu.g of lixisenatide.
Insulin Glargine
[1263] Insulin glargine was self-administered once daily at any
time of the day but at about the same time every day. The initial
daily dose of insulin glargine during the first week of treatment
was 10 U.
Dose Adjustment (Fixed Ratio Combination and Insulin Glargine)
[1264] The same dose adjustment algorithm was recommended for fixed
ratio combination and insulin glargine and was based on patient's
need for insulin. After the first week, the dose was titrated once
a week to reach and maintain a target fasting self-monitored plasma
glucose (SMPG) of 80 to 100 md/dL (4.4 to 5.6 mmol/L) while
avoiding hypoglycemia.
[1265] In the combination group, Pen A was to be used for total
daily doses between 10 and 40 units/day, and Pen B was to be used
for total daily doses between 41 and 60 units/day
Lixisenatide
[1266] Lixisenatide was self-administered once daily in the hour (0
to 60 minutes) before breakfast or the evening meal.
[1267] Lixisenatide started with once daily injection of 10 .mu.g
for 2 weeks, and then was continued with the maintenance dose of 20
.mu.g once daily from week 2 up to the end of the treatment
period.
Non investigational medicinal product(s) (NIMPs): Background
treatment: Metformin Formulation: Metformin tablets Route(s) of
administration: Administered orally according to its locally
approved label
[1268] Metformin was a mandatory background therapy. If taken,
previous oral antidiabetic treatments other than metformin were
discontinued from Visit 2. Patients in all 3 treatment groups
continued metformin during the study. Daily metformin dose was
increased weekly during the run-in phase by increments of up to 500
mg to a final daily dose of at least 2000 mg or up to the maximal
tolerated dose, which had to be 1500 mg/day to allow randomization.
After randomization (during the treatment period), this dose was
maintained until the end of the study unless there was a specific
safety issue related to this treatment.
Rescue Therapy:
[1269] Routing measurements and central lab alerts were set up to
ensure that glycemic parameters remained under thresholds values
predefined for rescue therapy. If values were above these
thresholds, and no explanations were found, or appropriate actions
failed, or a dose>60 U was necessary to decrease glycemic
parameters below the threshold values, rescue therapy was to be
introduced along with IMP and metformin (if taken). Newly initiated
anti-diabetic medications, or an increase from baseline in
background metformin dose were considered as rescue therapy.
Duration of treatment: Up to 30 weeks Duration of observation: Up
to 37 weeks (up to 6-week screening period+30-week randomized
treatment period+3-day post treatment safety follow-up period)
Criteria for Evaluation:
Efficacy:
[1270] Primary efficacy endpoint: Change in HbA1c from baseline to
Week 30
[1271] Key secondary efficacy endpoints: percent of patients with
Hb1Ac<7% or 6.5% at Week 30, change from baseline to Week 30
plasma glucose (FPG), body weight, and average 7-point SMPG,
percentage of patients reaching HbA1c<7% with no body weight
gain at Week 30; percentage of patients reaching HbA1c<7% with
no body weight gain at Week 30 and no documented symptomatic
hypoglycemia during the treatment period; insulin glargine dose at
Week 30.
Safety:
[1272] Symptomatic hypoglycemia [1273] Documented: typical symptoms
of hypoglycemia with a plasma glucose concentration 70 mg/dL (3.9
mmol/L). [1274] Probably: symptoms of hypoglycemia without plasma
glucose determination, but presumably caused by a plasma glucose
concentration 70 mg/dL (3.9 mmol/L) [1275] Severe: event requiring
assistance of another person to actively administer carbohydrate,
glucagon, or other resuscitative actions [1276] Treatment-emergent
adverse events (TEAE): serious TEAEs, TEAEs leading to death, TEAEs
leading to treatment discontinuation, adverse events of special
interest (i.e., alanine aminotransferase [ALT] increase, pregnancy,
symptomatic overdose with IMP/NIMP), major cardiovascular events,
potential allergic reactions, pancreatic events (confirmed
increased amylase/lipase>2.times.ULN, pancreatitis, pancreatic
neoplasm), events of confirmed increased calcitonin.gtoreq.20 pg/mL
(5.9 pmol/L), pen-related events [1277] Safety laboratory data
(hematology, clinical chemistry, lipase/amylase and calcitonin)
Statistical Methods:
[1278] Efficacy analysis was based on modified intent-to-treat
(mITT) population using efficacy assessments collected during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy. The mITT population consisted of
all randomized patients who had both a baseline assessment and at
least one post-baseline assessment of any primary or secondary
efficacy variables.
[1279] The primary efficacy endpoint was analyzed using a
mixed-effect model with repeated measures (MMRM). The MMRM model
included the treatment groups, randomization strata, visit,
treatment-by-visit interaction, and country as fixed-effect
factors, and the baseline HbA1c-by-visit interaction as covariate.
The adjusted mean change in HbA1c from baseline to Week 30 for each
treatment group was estimated in the framework of this model, as
well as the between-group difference and the 95% confidence
interval (CI for the adjusted mean).
[1280] Similar MMRM method or ANCOVA was applied on continuous
secondary efficacy endpoints and Cochran-Mantei-Haenszel method
stratified by randomization strata was applied on categorical
efficacy endpoints.
[1281] A step-down testing procedure was applied in order to
control the type 1 error. Once the co-primary hypotheses of
statistical superiority of insulin glargine/lixisenatide fixed
ratio combination to lixisenatide alone and the non-inferiority of
insulin glargine/lixisenatide fixed ratio combination to insulin
glargine alone were both established for the primary efficacy
endpoint, testing was performed according to the following order:
2-hour glucose excursion and body weight compared to insulin
glargine, FPG and daily average of the 7-point SMPG compared to
lixisenatide, superiority test compared to insulin glargine for the
percentage of patients reaching HbA1c<7% with no body weight
gain, HbA1c, daily average of the 7-point SMPG, percentage of
patients reaching HbA1c<7% with no body weight gain and no
documented symptomatic hypoglycemia, insulin glargine dose, and
FPG. When a test was not statistically significant at the 5% level,
subsequent tests were not performed.
SUMMARY
[1282] Population characteristics: A total of 1170 patients were
randomized to one of the three treatment groups (469 in the insulin
glargine/lixisenatide fixed ratio combination group, 467 in the
insulin glargine group and 234 in the lixisenatide group).
[1283] One randomized patient was not exposed to the study
treatment (patient's request) and 3 randomized patients were not
included in the mITT population due to a lack of post baseline
efficacy data. Demographics and baseline characteristics were
generally similar across the three treatment groups. The median age
was 59.0 years, the mean diabetes duration was 9 years and the mean
BMI was 32 kg/m.sup.2. The study population was primarily Caucasian
(90.1%), and 49.4% of the population were female patients (Table
3).
Efficacy Results:
Primary Efficacy Endpoint:
[1284] The primary objectives of the study were met as the
non-inferiority and superiority of the fixed ratio combination
compared to insulin glargine on HbA1c change from baseline to Week
30 was demonstrated as well as statistical superiority of the fixed
ratio combination over lixisenatide.
[1285] The least squared (LS) mean changes from baseline to Week 30
in HbA1c were -1.63% for the fixed ratio combination group, -1.34%
for the insulin glargine group, and -0.85% for the lixisenatide
group, reaching mean HbA1c levels of 6.5%, 6.8% and 7.3% at Week
30, respectively.
[1286] Statistical superiority of the fixed ratio combination over
lixisenatide was demonstrated for the co-primary end point (LS mean
difference versus lixisenatide=-0.78%; 95% CI=[-0.898% to
-0.665%]). p<0.0001).
[1287] LS mean difference between the combination group and insulin
glargine group was -0.29%, 95% CI=[-0.384% to -0.194%]. Based on
the pre-specified primary analysis, the non-inferiority of the
combination group compared to the insulin glargine group was
demonstrated, as the upper bound of the 2-sided 95% CI of the LS
mean difference was less than the predefined non-inferiority margin
of 0.3%. Statistical superiority of the combination over insulin
glargine was also demonstrated for this co-primary end point (LS
mean difference versus insulin glargine group=-0.29%;
p-value<0.0001) based on the step-down testing procedure.
Secondary Efficacy Endpoints:
[1288] Significantly more patients treated with the fixed ratio
combination reached an HbA1c<7% compared to those receiving
insulin glargine or lixisenatide: 73.7%, 59.4% and 33%,
respectively. The proportion difference (95% CI) versus insulin
glargine was 14.31% (8.37% to 20.25%) and 40.61% (33.63% to 47.59%)
versus lixisenatide. In addition, the proportion of patients
reaching HbA1c.ltoreq.6.5% was significantly higher in the
combination group (55.8%) than in the insulin glargine group
(39.5%) and the lixisenatide group (19.3%). The proportion
difference (95% CI) versus insulin glargine was 16.35% (10.13% to
22.58%) and 36.38% (29.81% to 42.95%) versus lixisenatide.
[1289] Treatment with the combination significantly improved
postprandial glycemic control during a standardized liquid
breakfast meal in comparison to insulin glargine as shown by the
results for the 2-hour glucose excursion (LS mean change was -2.31
and -0.18 mmol/L, respectively; LS mean difference (95% CI] versus
insulin glargine=-2.13 mmol/L [-2.498 mmol/L to -1.770 mmol/L],
p<0.0001). For the 2-hour PPG assessment the LS mean change was
-5.68 and -3.31 mmol/L, respectively; and the LS mean difference
[95% CI] versus insulin glargine was -2.38 mmol/L, [-2.794 mmol/L
to -1.963 mmol/L]). The corresponding results for the lixisenatide
group were -3.23 mmol/L for the LS mean change in 2-hour glucose
excursion and -4.58 mmol/L for the LS mean change in 2-hour PPG; LS
mean difference [95% CI] between combination and lixisenatide=0.91
mmol/L [0.448 mmol/L to 1.377 mmol/L] and -1.10 mmol/L[-1.627
mmol/L to -0.573 mmol/L]) respectively.
[1290] Body weight decreased in the fixed ratio combination and
lixisenatide groups and increased in the insulin glargine group
with a LS mean body weight change from baseline to Week 30 of
-0.29, -2.30 and +1.10 kg for each group respectively. A
statistically significant difference in the body weight change from
baseline to Week 30 was found between the fixed ratio combination
group and the insulin glargine group (LS mean difference=-1.40 kg;
95% CI: [-1.891 to -0.910]; p<0.0001).
[1291] The LS mean reductions from baseline to Week 30 in FPG were
similar in the fixed ratio combination (-3.46 mmol/L) and the
insulin glargine group (-3.27 mmol/L), and it was lower (-1.50
mmol/L) in the lixisenatide group. The LS mean difference of the
fixed ratio combination group versus insulin glargine was -0.19
mmol/L, 95% CI: [-0.420 to 0.038], p=0.1017), and versus
lixisenatide it was significantly greater (LS mean difference -1.96
mmol/L, 95% CI: [-2.246 to -1.682], p<0.0001).
[1292] Patients treated with fixed ratio combination had a
statistically significant greater decrease in average 7-point SMPG
profile compared to patients treated with insulin glargine and
patients treated with lixisenatide respectively (LS mean difference
versus insulin glargine=-0.69 mmol/L, 95% CI: [-0.892 to -0.495],
p<0.0001; LS mean difference versus lixisenatide=-1.40 mmol/L,
95% CI: [-1.645 to -1.158], p<0.0001). Graphical presentation of
the 7-point SMPG profiles showed a marked decrease in mean plasma
glucose at all time-points at Week 30 compared with the baseline in
all treatment groups. After 30 weeks of treatment, the 7-point SMPG
profiles showed that the mean values at all time-points were lower
in the fixed ratio combination group compared to the insulin
glargine group (except for the similar pre-breakfast value) and the
lixisenatide group, respectively (FIG. 6).
[1293] A higher proportion of patients reached the composite
endpoint of HbA1c<7.0% with no body weight gain at Week 30 in
the fixed ratio combination group (43.2%) compared to the insulin
glargine group (25.1%) and the lixisenatide group (27.9%),
respectively (proportion difference versus insulin glargine=18.08%,
95% CI=[12.15% to 24.01%], p<0.0001; proportion difference
versus lixisenatide=15.22%, 95% CI=[8.05% to 22.39%]), and the
difference between the combination group vs. insulin glargine was
statistically significant. More patients reached the triple
composite endpoint of HbA1c<7.0% with no body weight gain at
Week 30 and with no documented (plasma glucose concentration 70
mg/dL [3.9 mmol/L]) symptomatic hypoglycemia during the study in
the combination group (31.8%) compared to the insulin glargine
group (18.9%) and the lixisenatide group (26.2%), respectively
(proportion difference versus insulin glargine=12.98%, 95%
CI=[7.50% to 18.45%], p<0.0001; proportion difference versus
lixisenatide=5.61%, 95% CI=[-1.33% to 12.55%], and the difference
between the combination group vs. insulin glargine was
statistically significant.
[1294] At Week 30, the mean daily insulin glargine dose was similar
in the fixed ratio combination group and in the insulin glargine
group (fixed ratio combination: 39.77 U, insulin glargine: 40.46 U;
LS mean difference=-0.69 U; 95% CI=[-2.632 to 1.252]; p=0.4857)
(FIG. 7).
[1295] Seventeen (3.6%) patients in the fixed ratio combination
group, 16 (3.4%) patients in the insulin glargine group and 29
(12.4%) patients in the lixisenatide group received rescue
therapy.
Safety Results:
[1296] The fixed dose combination was well tolerated during the
30-week on-treatment period; the safety profile of the combination
arm reflected those of its components.
[1297] A total of 267 (56.9%) patients in the combination group,
227 (48.6%) in the insulin glargine group, and 157 (67.4%) in the
lixisenatide group reported treatment-emergent adverse events.
[1298] The most frequently occurring adverse events (AE)
(PT.gtoreq.5%) in the fixed ratio combination and the insulin
glargine and lixisenatide groups were nausea (9.6%, 3.6% and 24%),
diarrhea (9.0%, 4.3% and 9.0%) and upper respiratory tract
infection (7.0%, 4.9% and 5.2%).
[1299] The overall incidence of gastrointestinal adverse events was
21.7%, 12.6% and 36.9 in the combination, insulin glargine and
lixisenatide groups, respectively. Overall, 45 (9.6%) patients in
the combination group experienced nausea, compared with 17 (3.6%)
in the insulin glargine group and 56 (24%) in the lixisenatide
group.
[1300] Overall, 6 patients experienced at least 1 TEAE leading to
death: 2 from the fixed ratio combination group (PTs: Metastatic
lung cancer; Congestive cardiac failure), 3 from the insulin
glargine group (PTs: Acute myocardial infarction and Acute
pulmonary edema; Squamous cell carcinoma of the oral cavity) and 1
from the lixisenatide group (PT: Death) (Table 21).
[1301] Serious TEAEs were reported by a similar proportion of
patients in each treatment group: 18 (3.8%) patients in the
combination group, 19 (4.1%) in the insulin glargine group and 9
(3.9%) in the lixisenatide group (Table 22).
[1302] A higher number of patients withdrew from treatment due to
TEAEs in the lixisenatide group (9.0%) than from the combination
(2.6%) or insulin glargine (1.9%) groups. Most of these withdrawals
were caused by gastrointestinal adverse events in the lixisenatide
group (5.2%) compared to the combination (0.9%) and insulin
glargine (0.2%) groups (Table 23).
[1303] Injection site reactions during the on-treatment period were
reported by similarly low percentages of patients across the three
treatment groups (fixed ratio combination: (2.6%), insulin
glargine: (1.7%), and lixisenatide: (3.0%)) (Table 24). None were
considered serious. One patient in the lixisenatide group had
injection site erythema that led to treatment discontinuation.
[1304] Adverse events adjudicated as allergic reactions possibly
related to IMP by the Allergic Reaction Assessment Committee (ARAC)
were reported in 3 patients (0.6%) (PTs: Urticaria) in the fixed
ratio combination group, in 2 patients (0.9%) (PTs: Anaphylactic
reaction and Urticaria) in the lixisenatide group and none in the
in the insulin glargine group. Three patients (0.6%) reported
angioedema, all in the fixed ratio combination group, which were
adjudicated by the ARAC as allergic reactions not related to IMP
(Table 25).
[1305] There were no cases of pancreatitis positively adjudicated
by the Pancreatic Safety Assessment Committee (PSAC) (Table
26).
[1306] Two patients (0.4%) in the fixed ratio combination group, 7
patients (1.5%) in the insulin glargine group and 2 patients (0.9%)
in the lixisenatide group experienced TEAEs adjudicated as major
cardiovascular events by CAC during the on-treatment period (Table
27).
[1307] One case of pancreatic cancer was reported in the in insulin
glargine group. No thyroid carcinomas were reported in any
treatment group. One patient in the insulin glargine group reported
a TEAE of increased calcitonin (.gtoreq.20 pg/mL) versus none in
either the fixed ratio combination group or the lixisenatide group
(Table 28).
[1308] No symptomatic overdose with IMP was reported in any
treatment group during the on-treatment period.
[1309] One patient in the insulin glargine/lixisenatide fixed ratio
combination group, 2 patients in the insulin glargine group and 1
patient in the lixisenatide group experienced an AE of ALT increase
during the on-treatment period (Table 29). None of the events met
the definition for Hy's Law.
[1310] A total of 44 patients (fixed ratio combination: 25 (5.3%),
insulin glargine: 10 (2.1%) and lixisenatide: 9 (3.9%)) reported 54
pen-related events in the pen-related event questionnaire during
the on-treatment period. None was associated with a clinical event
(i.e., symptomatic hypoglycemic event, hyperglycemic adverse event
or other adverse event) (Table 30).
[1311] 27.3% of patients treated with the fixed ratio combination,
25.5% patients treated with insulin glargine, and 6.4% patients
treated with lixisenatide reported 409, 338, and 46 symptomatic
hypoglycemia events according to protocol definition on the
specific hypoglycemia page (Table 31). The number of symptomatic
events per patient-year was 1.55 in the fixed ratio combination
group, 1.29 in the insulin glargine group and 0.37 in the
lixisenatide group. When considering documented (70 mg/dL)
symptomatic hypoglycemia, the incidence was 25.6% in the
combination group, 23.6% in the insulin glargine group and 6.4% in
the lixisenatide group with a corresponding event rate per
patient-year of 1.44, 1.22 and 0.34 respectively.
[1312] Only 1 event of severe symptomatic hypoglycemia was reported
during the study and occurred in the insulin glargine group.
Preliminary Conclusions:
[1313] In conclusion, the primary objectives of the study were met
as the non-inferiority and superiority of the fixed ratio
combination compared to insulin glargine on HbA1c change from
baseline to Week 30 was demonstrated as well as statistical
superiority of the fixed ratio combination over lixisenatide. The
fixed ratio combination added to metformin for patients not well
controlled with metformin with or without a second OAD
significantly improved HbA1c and reduced 2-hour glucose excursions
and 2-hour PPG, average 7-point SMPG and body weight in comparison
to insulin glargine. The combination also significantly improved
HbA1c, FPG, and average 7-point SMPG in comparison with
lixisenatide.
[1314] In summary the fixed ratio combination was well tolerated.
Nausea was the most frequently reported adverse event in the
combination group but was reported less frequently than in the
lixisenatide group. The incidence of symptomatic hypoglycemia was
similar in the combination and insulin glargine treatment groups
and lower in the lixisenatide group, as expected. The safety
profile of the combination group reflected those of its component
parts.
[1315] The advantages of starting with the fixed ratio combination
compared to starting with each component alone in patients not well
controlled on OAD is therefore evidenced based on the advantages
demonstrated for HbA1c and body weight vs insulin glargine, and for
HbA1c, FPG and gastrointestinal tolerability (descriptive analysis)
in comparison to lixisenatide.
3 Results
3.1 Study Patients
3.1.1 Patient Accountability
[1316] Of the 2457 patients screened, 1170 were randomized to one
of the three treatment groups (469 in the combination group, 467 in
the insulin glargine group and 234 in the lixisenatide group) in
240 centers distributed among 23 countries (Australia, Belgium,
Canada, Chile, Czech Republic, Denmark, Estonia, France, Germany,
Hungary, Italy, Latvia, Lithuania, Mexico, Poland, Romania, Russian
federation, South Africa, Spain, Sweden, Ukraine, United Kingdom
and United States of America). The main reason for screening
failure was HbA1c value at screening visit out of the protocol
defined range (653 [26.6%] out of 2457 screened patients).
[1317] A total 1169 randomized patients were exposed to open-label
treatment and 1167 patients were included in the mITT population
for efficacy analyses (Table 1). One patient was randomized but not
treated by the patient request. Three randomized patients (1 in
each treatment group) were not included in the mITT population
because they did not have any post baseline efficacy data.
TABLE-US-00008 TABLE 1 Analysis populations Fixed Ratio Insulin
Combination Glargine Lixisenatide All Randomized population 469
(100%) 467 (100%) 234 (100%) 1170 (100%) Efficacy population 468
(99.8%) 466 233 1167 (99.7%) Modified Intent-to-Treat (mITT)
(99.8%) (99.6%) Safety population 469 467 233 1169 Note: The safety
population patients are tabulated according to treatment actually
received (as treated).
[1318] For the efficacy population, patients are tabulated
according to their randomized treatment. There is no patient
randomized in a group and taking another study treatment. The study
design is described in FIG. 8.
3.1.2 Study Disposition
TABLE-US-00009 [1319] TABLE 2 Patient disposition-Randomized
population Fixed Ratio Insulin Combination Glargine Lixisenatide (N
= 469) (N = 467) (N = 234) Randomized and treated 469 (100%) 467
(100%) 233 (99.6%) Completed the open-label study 440 (93.8%) 440
(94.2%) 205 (87.6%) treatment period Did not complete the
open-label 29 (6.2%) 27 (5.8%) 28 (12.0%) study treatment period
Subject's decision for treatment 25 (5.3%) 17 (3.6%) 18 (7.7%)
discontinuation Reason for study treatment discontinuation Adverse
event 12 (2.6%) 9 (1.9%) 21 (9.0%) Lack of efficacy 1 (0.2%) 0 3
(1.3%) Poor compliance to protocol 8 (1.7%) 9 (1.9%) 4 (1.7%) Lost
to follow-up 0 0 0 Other reasons 8 (1.7%) 9 (1.9%) 0 Status at last
study contact Alive 467 (99.6%) 462 (98.9%) 233 (99.6%) Dead 2
(0.4%) 4 (0.9%) 1 (0.4%) Lost to follow-up 0 1 (0.2%) 0 Note:
Percentages are calculated using the number of patients randomized
as denominator.
3.1.3 Demographics and Baseline Characteristics
TABLE-US-00010 [1320] TABLE 3 Demographics and patient
characteristics at screening or baseline- Randomized population
Fixed Ratio Insulin Combination Glargine Lixisenatide All (N = 469)
(N = 467) (N = 234) (N = 1170) Age (years) Number 469 467 234 1170
Mean (SD) 58.2 (9.5) 58.3 (9.4) 58.7 (8.7) 58.4 (9.3) Median 59.0
59.0 59.0 59.0 Min:Max 18:79 25:82 31:80 18:82 Age group (years) [n
(%)] Number 469 467 234 1170 <50 86 (18.3%) 82 28 196 (16.8%)
(17.6%) (12.0%) .gtoreq.50 to <65 250 (53.3%) 271 147 668
(57.1%) (58.0%) (62.8%) .gtoreq.65 to <75 121 (25.8%) 97 53 271
(23.2%) (20.8%) (22.6%) .gtoreq.75 12 (2.6%) 17 (3.6%) 6 (2.6%) 35
(3.0%) Gender [n (%)] Number 469 467 234 1170 Male 222 (47.3%) 237
133 592 (50.6%) (50.7%) (56.8%) Female 247 (52.7%) 230 101 578
(49.4%) (49.3%) (43.2%) Race [n (%)] Number 469 467 234 1170
Caucasian 417 (88.9%) 421 216 1054 (90.1%) (92.3%) (90.1%) Black 33
(7.0%) 33 (7.1%) 12 (5.1%) 78 (6.7%) Asian/Oriental 8 (1.7%) 7
(1.5%) 3 (1.3%) 18 (1.5%) Other 11 (2.3%) 6 (1.3%) 3 (1.3%) 20
(1.7%) Ethnicity [n (%)] Number 469 467 234 1170 Hispanic 85
(18.1%) 87 51 223 (19.1%) (18.6%) (21.8%) Not Hispanic 384 (81.9%)
380 183 947 (80.9%) (81.4%) (78.2%) HbA1c (%) at visit 1 (week -6)
Number 469 467 233 1169 Mean (SD) 8.17 (0.70) 8.20 (0.68) 8.28
(0.70) 8.20 (0.69) Median 8.10 8.10 8.20 8.10 Min:Max 6.8:10.4
7.0:10.0 7.0:10.0 6.8:10.4 HbA1c (%) at visit 4 (week -1) Number
469 467 234 1170 Mean (SD) 8.11 (0.67) 8.13 (0.65) 8.16 (0.69) 8.13
(0.67) Median 8.10 8.00 8.10 8.10 Min:Max 7.0:9.8 7.0:10.0 7.0:10.0
7.0:10.0 Randomization strata of HbA1c (%) at visit 4 (week -1) [n
(%)] Number 469 467 234 1170 <8 207 (44.1%) 207 103 517 (44.2%)
(44.3%) (44.0%) .gtoreq.8 262 (55.9%) 260 131 653 (55.8%) (55.7%)
(56.0%) Randomization strata of second OAD use at screening [n (%)]
Number 469 467 234 1170 Yes 291 (62.0%) 288 146 725 (62.0%) (61.7%)
(62.4%) No 178 (38.0%) 179 88 445 (38.0%) (38.3%) (37.6%) Baseline
BMI (kg/m.sup.2) Number 469 467 234 1170 Mean (SD) 31.64 (4.40)
31.66 (4.51) 31.99 (4.39) 31.72 (4.44) Median 31.40 31.45 32.09
31.53 Min:Max 18.9:40.1 21.0:41.5 20.2:40.3 18.9:41.5 Baseline BMI
categories (kg/m.sup.2) [n (%)] Number 469 467 234 1170 <30 174
(37.1%) 179 75 428 (36.6%) (38.3%) (32.1%) .gtoreq.30 295 (62.9%)
288 159 742 (63.4%) (61.7%) (67.9%) BMI = Body Mass Index, OAD =
Oral anti-diabetic drug.
TABLE-US-00011 TABLE 4 Disease characteristics at screening or
baseline-Randomized population Fixed Ratio Insulin Combination
Glargine Lixisenatide All (N = 469) (N = 467) (N = 234) (N = 1170)
Duration of diabetes (years) Number 469 467 234 1170 Mean (SD) 8.89
(5.51) 8.66 (5.59) 8.89 (6.26) 8.80 (5.69) Median 8.14 7.60 7.65
7.69 Min:Max 1.0:34.2 1.0:39.7 1.0:44.5 1.0:44.5 Age at onset of
Type 2 diabetes (years) Number 469 467 234 1170 Mean (SD) 49.3
(9.8) 49.6 (8.8) 49.7 (9.1) 49.5 (9.3) Median 50.0 50.0 50.0 50.0
Min:Max 14:75 17:76 22:74 14:76 History of gestational diabetes [n
(%)] Number (Female) 247 230 101 578 Yes (Female) 20 (8.1%) 12
(5.2%) 6 (5.9%) 38 (6.6%) No (Female) 227 (91.9%) 218 95 540
(93.4%) (94.8%) (94.1%) Duration of metformin treatment (years)
Number 466 466 232 1164 Mean (SD) 6.42 (4.85) 6.46 (4.70) 6.12
(4.45) 6.38 (4.71) Median 5.25 5.45 5.45 5.37 Min:Max 0.3:34.2
0.3:26.4 0.2:24.7 0.2:34.2 Daily dose of metformin at baseline (mg)
Number 469 467 234 1170 Mean (SD) 2246.1 2244.7 2267.3 2249.8
(456.8) (444.7) (427.4) (445.9) Median 2000.0 2000.0 2000.0 2000.0
Min:Max 1000:3000 1000:3000 1000:3000 1000:3000 Categorized daily
dose of metformin at baseline (mg) [n (%)] Number 469 467 234 1170
<1500 3 (0.6%) 4 (0.9%) 1 (0.4%) 8 (0.7%) .gtoreq.1500-<2500
283 (60.3%) 285 139 707 (60.4%) (61.0%) (59.4%)
.gtoreq.2500-<3000 98 (20.9%) 98 55 251 (21.5%) (21.0%) (23.5%)
.gtoreq.3000 85 (18.1%) 80 39 204 (17.4%) (17.1%) (16.7%) Second
OAD use at screening by class [n (%)] Number (Yes) 274 (58.4%) 270
133 677 (57.9%) (57.8%) (56.8%) Sulfonylurea 259 (55.2%) 249 123
631 (53.9%) (53.3%) (52.6%) Glinide 3 (0.6%) 10 (2.1%) 5 (2.1%) 18
(1.5%) SGLT-2 inhibitor 2 (0.4%) 2 (0.4%) 0 4 (0.3%) DPP-4
inhibitor 12 (2.6%) 11 (2.4%) 5 (2.1%) 28 (2.4%) Duration of second
OAD treatment (years) Number 274 269 133 676 Mean (SD) 3.98 (4.07)
4.61 (4.67) 3.94 (3.54) 4.22 (4.23) Median 2.59 3.26 2.49 2.82
Min:Max 0.3:21.3 0.3:25.4 0.3:16.0 0.3:25.4 Prior use of GLP-1
receptor agonist [n (%)] Number 469 467 234 1170 Yes 15 (3.2%) 21
(4.5%) 10 (4.3%) 46 (3.9%) No 454 (96.8%) 446 224 1124 (96.1%)
(95.5%) (95.7%) Prior use of insulin [n (%)] Number 469 467 234
1170 Yes 11 (2.3%) 14 (3.0%) 4 (1.7%) 29 (2.5%) No 458 (97.7%) 453
230 1141 (97.5%) (97.0%) (98.3%) Diabetic retinopathy [n (%)]
Number 469 467 234 1170 Yes 44 (9.4%) 27 (5.8%) 26 97 (8.3%)
(11.1%) Photocoagulation 4 (0.9%) 2 (0.4%) 0 6 (0.5%) performed:
Yes Photocoagulation 39 (8.3%) 25 (5.4%) 23 (9.8%) 87 (7.4%)
performed: No Photocoagulation 1 (0.2%) 0 3 (1.3%) 4 (0.3%)
performed: Unknown Vitrectomy performed 0 0 0 0 because of diabetic
retinopathy: Yes Vitrectomy performed 42 (9.0%) 27 (5.8%) 22 (9.4%)
91 (7.8%) because of diabetic retinopathy: No Vitrectomy performed
2 (0.4%) 0 4 (1.7%) 6 (0.5%) because of diabetic retinopathy:
Unknown No 416 (88.7%) 429 199 1044 (89.2%) (91.9%) (85.0%) Unknown
9 (1.9%) 11 (2.4%) 9 (3.8%) 29 (2.5%) Diabetic sensory or motor
neuropathy [n (%)] Number 469 467 234 1170 Yes 111 (23.7%) 98 51
260 (22.2%) (21.0%) (21.8%) No 347 (74.0%) 360 180 887 (75.8%)
(77.1%) (76.9%) Unknown 11 (2.3%) 9 (1.9%) 3 (1.3%) 23 (2.0%)
Diabetic autonomic neuropathy [n (%)] Number 469 467 234 1170 Yes 5
(1.1%) 5 (1.1%) 3 (1.3%) 13 (1.1%) No 450 (95.9%) 453 224 1127
(96.3%) (97.0%) (95.7%) Unknown 14 (3.0%) 9 (1.9%) 7 (3.0%) 30
(2.6%) Diabetic nephropathy [n (%)] Number 469 467 234 1170 Yes 33
(7.0%) 13 (2.8%) 8 (3.4%) 54 (4.6%) Impaired renal 2 (0.4%) 0 1
(0.4%) 3 (0.3%) function (estimated GFR by MDRD below 60 ml/min)
Microalbuminuria (30 23 (4.9%) 8 (1.7%) 7 (3.0%) 38 (3.2%) to 299
mcg per mg creatinine) Overt proteinuria 7 (1.5%) 5 (1.1%) 0 12
(1.0%) (equal to or above 300 mcg per mg creatinine) No 424 (90.4%)
445 218 1087 (92.9%) (95.3%) (93.2%) Unknown 12 (2.6%) 9 (1.9%) 8
(3.4%) 29 (2.5%) Baseline urinary albumin/creatinine ratio
(.mu.g/mg) [n (%)] Number 466 466 234 1166 <30 (normal) 365
(78.3%) 380 187 932 (79.9%) (81.5%) (79.9%) .gtoreq.30-<300 89
(19.1%) 74 41 204 (17.5%) (microalbuminuria) (15.9%) (17.5%)
.gtoreq.300 12 (2.6%) 12 (2.6%) 6 (2.6%) 30 (2.6%)
(macroalbuminuria) Creatinine clearance at screening (mL/min)
Number 465 464 232 1161 Mean (SD) 116.02 115.10 116.50 115.75
(34.99) (36.25) (33.12) (35.12) Median 109.93 107.86 114.02 110.42
Min:Max 51.8:263.9 49.3:255.0 46.6:239.0 46.6:263.9 Creatinine
clearance (mL/min) categories at screening [n (%)] Number 465 464
232 1161 <15 (end stage renal 0 0 0 0 disease) .gtoreq.15-<30
(severe 0 0 0 0 decrease in GFR) .gtoreq.30-<60 (moderate 4
(0.9%) 3 (0.6%) 3 (1.3%) 10 (0.9%) decrease in GFR)
.gtoreq.60-<90 (mild 117 (25.2%) 128 44 289 (24.9%) decrease in
GFR) (27.6%) (19.0%) .gtoreq.90 (normal) 344 (74.0%) 333 185 862
(74.2%) (71.8%) (79.7%) OAD = Oral anti-diabetic drug, SGLT-2 =
Sodium glucose co-transporter 2, DPP-4 = Dipeptidyl-peptidase 4,
GLP-1 = Glucagon like peptide-1, GFR = glomerular filtration rate.
Creatinine clearance value is derived using the equation of
Cockroft and Gault. Albumin/creatinine ratio is presented in
.mu.g/mg, equivalent to mg/g, and the conversion factor to the
standard international unit mg/mmol is 0.1130.
3.1.4 Dosage and Duration of Investigational Medicinal Product
TABLE-US-00012 [1321] TABLE 5 Exposure to IMP-Safety population
Fixed Ratio Insulin Combination Glargine Lixisenatide (N = 469) (N
= 467) (N = 233) Cumulative duration of 261.5 261.2 124.6 treatment
exposure (patient years) Duration of study treatment (days) Number
468 467 232 Mean (SD) 204.1 (33.9) 204.3 (32.5) 196.1 (48.2) Median
211.0 211.0 211.0 Min:Max 2:252 1:249 6:224 Duration of study
treatment by category [n (%)] Missing duration 1 (0.2%) 0 1 (0.4%)
1-14 days 3 (0.6%) 4 (0.9%) 4 (1.7%) 15-28 days 3 (0.6%) 5 (1.1%) 3
(1.3%) 29-56 days 6 (1.3%) 2 (0.4%) 7 (3.0%) 57-84 days 3 (0.6%) 2
(0.4%) 3 (1.3%) 85-126 days 6 (1.3%) 5 (1.1%) 4 (1.7%) 127-168 days
6 (1.3%) 4 (0.9%) 2 (0.9%) 169-210 days 113 (24.1%) 200 (42.8%) 66
(28.3%) >210 days 328 (69.9%) 245 (52.5%) 143 (61.4%) Cumulative
duration of study treatment by category [n (%)] Missing duration 1
(0.2%) 0 1 (0.4%) .gtoreq.1 day 468 (99.8%) 467 (100%) 232 (99.6%)
.gtoreq.15 days 465 (99.1%) 463 (99.1%) 228 (97.9%) .gtoreq.29 days
462 (98.5%) 458 (98.1%) 225 (96.6%) .gtoreq.57 days 456 (97.2%) 456
(97.6%) 218 (93.6%) .gtoreq.85 days 453 (96.6%) 454 (97.2%) 215
(92.3%) .gtoreq.127 days 447 (95.3%) 449 (96.1%) 211 (90.6%)
.gtoreq.169 days 441 (94.0%) 445 (95.3%) 209 (89.7%) .gtoreq.211
days 328 (69.9%) 245 (52.5%) 143 (61.4%) IMP: Investigational
Medicinal Product Duration of exposure = (date of the last
open-label IMP injection-date of the first open-label IMP
injection) + 1. Note: Patients are considered in the treatment
group they actually received at randomization.
TABLE-US-00013 TABLE 6 Number (%) of patients by final insulin dose
at the end of the open-label treatment-Safety population Fixed
Ratio Insulin Final Combination Glargine Insulin Dose (N = 469) (N
= 467) <20 U 59 (12.6%) 43 (9.2%) .gtoreq.20 U to <30 U 76
(16.2%) 96 (20.6%) .gtoreq.30 U to .ltoreq.40 U 126 (26.9%) 117
(25.1%) >40 U to .ltoreq.60 U 208 (44.3%) 209 (44.8%) >60 U 0
2 (0.4%) =60 U 73 (15.6%) 94 (20.1%) <20 U 59 (12.6%) 43 (9.2%)
Pen A .sup.a <20 U 59 (12.6%) .gtoreq.20 U to <30 U 75
(16.0%) .gtoreq.30 U to .ltoreq.40 U 104 (22.2%) >40 U to
.ltoreq.60 U 2 (0.4%) >60 U 0 Pen B .sup.b <20 U 0 .gtoreq.20
U to <30 U 0 .gtoreq.30 U to .ltoreq.40 U 21 (4.5%) >40 U to
.ltoreq.60 U 206 (43.9%) >60 U 0 .sup.a 2 U/1 .mu.g fixed ratio
for insulin glargine/lixisenatide intended to administer daily
doses between 10 and 40 U (10 U/5 .mu.g and 40 U/20 .mu.g) .sup.b 3
U/1 .mu.g fixed ratio for insulin glargine/lixisenatide intended to
administer daily doses between 41 and 60 U (.apprxeq.41 U/14 .mu.g
and 60 U/20 .mu.g) Note: Percentages are calculated using the
number of safety patients as the denominator.
TABLE-US-00014 TABLE 7 Number (%) of fixed ratio combination
patients by final lixisenatide dose at the end of open-label
treatment-Safety population Fixed Ratio Final Combination
Lixisenatide Dose (N = 469) <10 .mu.g 59 (12.6%) .gtoreq.10
.mu.g to <15 .mu.g 131 (27.9%) .gtoreq.15 .mu.g to .ltoreq.20
.mu.g 275 (58.6%) <10 .mu.g 59 (12.6%) >20 .mu.g 2 (0.4%) Pen
A .sup.a <10 .mu.g 59 (12.6%) .gtoreq.10 .mu.g to <15 .mu.g
75 (16.0%) .gtoreq.15 .mu.g to .ltoreq.20 .mu.g 104 (22.2%) >20
.mu.g 2 (0.4%) Pen B .sup.b .gtoreq.10 .mu.g to <15 .mu.g 56
(11.9%) .gtoreq.15 .mu.g to .ltoreq.20 .mu.g 171 (36.5%) .sup.a 2
U/1 .mu.g fixed ratio for insulin glargine/lixisenatide intended to
administer daily doses between 10 and 40 U (10 U/5 .mu.g and 40
U/20 .mu.g) .sup.b 3 U/1 .mu.g fixed ratio for insulin
glargine/lixisenatide intended to administer daily doses between 41
and 60 U (.apprxeq.41 U/14 .mu.g and 60 U/20 .mu.g) Note:
Percentages are calculated using the number of safety patients as
the denominator.
TABLE-US-00015 TABLE 8 Number (%) of patients by final lixisenatide
dose at the end of open-label treatment- Safety population Final
Lixisenatide Lixisenatide Dose (N = 233) 10 .mu.g 26 (11.2%) 20
.mu.g 207 (88.8%) Note: Percentages are calculated using the number
of safety patients as the denominator.
3.2 Efficacy
3.2.1 Primary Efficacy Endpoint
TABLE-US-00016 [1322] TABLE 9 Mean change in HbA1c (%) from
baseline to Week 30 using MMRM-mITT population (FIGS. 1 and 2)
Fixed Ratio Insulin Combination Glargine Lixisenatide HbA1c (%) (N
= 468) (N = 466) (N = 233) Baseline Number 467 464 233 Mean (SD)
8.08 (0.71) 8.08 (0.69) 8.13 (0.72) Median 8.00 8.00 8.00 Min:Max
4.5:10.2 5.9:10.4 6.7:10.3 Week 30 Number 443 446 221 Mean (SD)
6.50 (0.75) 6.81 (0.76) 7.31 (0.87) Median 6.30 6.70 7.20 Min:Max
4.9:9.6 4.6:10.7 5.2:11.0 Change from baseline to Week 30 Number
467 464 233 LS Mean (SE).sup.a -1.63 (0.038) -1.34 (0.039) -0.85
(0.052) LS mean difference (SE) -0.29 (0.048) -- -- vs insulin
glargine.sup.a 95% Cl (-0.384 to -0.194) -- -- p-value <0.0001
-- -- LS mean difference (SE) -0.78 (0.059) -- -- vs
lixisenatide.sup.a 95% Cl (-0.898 to -0.665) -- -- p-value
<0.0001 -- -- .sup.aMixed-effect model with repeated measures
(MMRM) with treatment groups (fixed ratio combination, insulin
glargine alone, lixisenatide alone), randomization strata of HbA1c
(<8.0%, .gtoreq.8.0%) at Visit 4 (Week -1), randomization strata
of second OAD use at screening (Yes, No), visit (Week 8, 12, 24,
and 30), treatment-by-visit interaction, and country as fixed
effects, and baseline HbA1c value-by-visit interaction as a
covariate.
[1323] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1324] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy.
[1325] Included are patients who have measurements at baseline and
post-baseline.
3.2.2 Other Key Efficacy Endpoints
TABLE-US-00017 [1326] TABLE 10 Number (%) of patients with HbA1c
value .ltoreq.6.5% or <7.0% at Week 30-mITT population Fixed
Ratio Insulin Combination Glargine Lixisenatide HbA1c (%) (N = 468)
(N = 466) (N = 233) Number 468 466 233 .ltoreq.6.5% 261 (55.8%) 184
(39.5%) 45 (19.3%) Proportion difference 16.35% (10.13% -- -- (95%
Cl) vs. insulin to glargine.sup.a 22.58%) Proportion difference
36.38% (29.81% -- -- (95% Cl) vs. to lixisenatide.sup.a 42.95%)
<7% 345 (73.7%) 277 (59.4%) 77 (33.0%) Proportion difference
14.31% (8.37% -- -- (95% Cl) vs. insulin to glargine.sup.a 20.25%)
Proportion difference 40.61% (33.63% -- -- (95% Cl) vs. to
lixisenatide.sup.a 47.59%) .sup.aWeighted average of proportion
difference between treatment groups (fixed ratio combination,
insulin glargine, lixisenatide) from each strata (randomization
strata of HbA1c [<8.0, .gtoreq.8.0%] at Visit 4 (Week -1),
randomization strata of second OAD use at screening [Yes, No])
using Cochran-Mantel-Haenszel (CMH) weights. Proportion difference
= difference of the proportions of patients achieving HbA1c value
.ltoreq.6.5% or <7%
[1327] All measurements at Week 30 were used, including those
obtained after IMP discontinuation or introduction of rescue
therapy. If no assessment was available at Week 30 at all, patients
were treated as non-responders.
TABLE-US-00018 TABLE 11 Mean change in 2-hour plasma glucose
excursion (mmol/L) during a standardized meal test from baseline to
Week 30 using ANCOVA-mITT population Fixed Ratio Insulin 2-hour
plasma glucose Combination Glargine Lixisenatide excursion (mmol/L)
(N = 468) (N = 466) (N = 233) Baseline Number 428 425 192 Mean (SD)
5.31 (2.86) 5.02 (2.96) 5.07 (2.54) Median 5.20 4.90 5.00 Min:Max
-4.3:14.2 -4.7:14.5 -3.2:12.2 Week 30 (LOCF) Number 428 425 192
Mean (SD) 2.81 (2.84) 4.80 (2.90) 1.70 (3.23) Median 2.80 4.70 1.05
Min:Max -4.3:12.3 -5.5:14.4 -5.0:10.2 Change from baseline to Week
30 (LOCF) Number 428 425 192 Mean (SD) -2.49 (3.37) -0.22 (2.86)
-3.37 (3.41) Median -2.40 -0.10 -3.45 Min:Max -12.2:10.1 -13.1:7.9
-12.4:4.8 LS Mean (SE).sup.a -2.31 (0.154) -0.18 (0.157) -3.23
(0.216) LS mean difference (SE) -2.13 (0.185) -- -- vs insulin
glargine.sup.a 95% Cl (-2.498 to -1.770) -- -- p-value <0.0001
-- -- LS mean difference (SE) 0.91 (0.237) -- -- vs
lixisenatide.sup.a 95% Cl (0.448 to 1.377) -- -- LOCF = Last
observation carried forward. .sup.aAnalysis of covariance (ANCOVA)
model with treatment groups (fixed ratio combination, insulin
glargine, lixisenatide), randomization strata of HbA1c (<8.0%,
.gtoreq.8.0%) at Visit 4 (Week -1), randomization strata of second
OAD use at screening (Yes, No), and country as fixed effects and
baseline 2-hour plasma glucose excursion value as a covariate.
[1328] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1329] The analysis included measurements collected during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy.
[1330] Patients injecting IMP in the morning in the lixisenatide
group and all patients in fixed ratio combination or insulin
glargine group with both baseline and Week 30 (LOCF) measurements
were included.
TABLE-US-00019 TABLE 12 Mean change in 2-hour postprandial plasma
glucose (mmol/L) during a standardized meal test from baseline to
Week 30 using ANCOVA-mITT population 2-hour postprandial Fixed
Ratio Insulin plasma Combination Glargine Lixisenatide glucose
(mmol/L) (N = 468) (N = 466) (N = 233) Baseline Number 430 430 196
Mean (SD) 15.19 (3.63) 14.61 (3.64) 14.72 (3.32) Median 15.20 14.50
14.70 Min:Max 3.1:24.6 4.4:26.6 4.9:24.1 Week 30 (LOCF) Number 430
430 196 Mean (SD) 9.15 (3.20) 11.35 (3.12) 9.99 (3.91) Median 8.90
11.20 9.45 Min:Max 2.8:24.0 3.3:19.9 4.0:25.8 Change from baseline
to Week 30 (LOCF) Number 430 430 196 Mean (SD) -6.04 (4.27) -3.26
(3.54) -4.73 (4.11) Median -6.00 -3.35 -5.05 Min:Max -18.1:6.7
-17.2:6.3 -13.8:8.4 LS Mean (SE).sup.a -5.68 (0.176) -3.31 (0.178)
-4.58 (0.245) LS mean difference (SE) -2.38 (0.212) -- -- vs
insulin glargine.sup.a 95% Cl (-2.794 to -1.963) -- -- LS mean
difference (SE) -1.10 (0.269) -- -- vs lixisenatide.sup.a 95% Cl
(-1.627 to -0.573) -- -- LOCF = Last observation carried forward.
.sup.aAnalysis of covariance (ANCOVA) model with treatment groups
(fixed ratio combination, insulin glargine, lixisenatide),
randomization strata of HbA1c (<8.0, .gtoreq.8.0%) at Visit 4
(Week -1), randomization strata of second OAD use at screening
(Yes, No), and country as fixed effects and baseline 2-hour
postprandial plasma glucose value as a covariate.
[1331] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1332] The analysis included measurements collected during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy.
[1333] Patients injecting IMP in the morning in the lixisenatide
group and all patients in fixed ratio combination or insulin
glargine group with both baseline and Week 30 (LOCF) measurements
were included.
TABLE-US-00020 TABLE 13 Mean change in body weight (kg) from
baseline to Week 30 using MMRM-mITT population (FIG. 3) Fixed Ratio
Insulin Body Combination Glargine Lixisenatide Weight (kg) (N =
468) (N = 466) (N = 233) Baseline Number 467 465 233 Mean (SD)
89.44 (17.16) 89.75 (16.34) 90.79 (16.25) Median 88.90 88.50 91.00
Min:Max 46.7:147.0 47.4:137.3 54.3:144.0 Week 30 Number 448 446 222
Mean (SD) 89.16 (17.34) 90.68 (16.03) 88.57 (16.20) Median 88.00
89.00 88.90 Min:Max 45.2:145.5 51.2:143.6 53.5:152.3 Change from
baseline to Week 30 Number 467 465 233 LS Mean (SE)a -0.29 (0.182)
1.11 (0.183) -2.30 (0.256) LS mean -1.40 (0.250) -- -- difference
(SE) vs insulin glargine.sup.a 95% Cl (-1.891 to -0.910) -- --
p-value <0.0001 -- -- LS mean 2.01 (0.307) -- -- difference (SE)
vs lixisenatide.sup.a 95% Cl (1.404 to 2.609) -- --
.sup.aMixed-effect model with repeated measures (MMRM) with
treatment groups (fixed ratio combination, insulin glargine alone,
lixisenatide alone), randomization strata of HbA1c (<8.0,
.gtoreq.8.0%) at Visit 4 (Week -1), randomization strata of second
OAD use at screening (Yes, No), scheduled visit, treatment-by-visit
interaction and country as fixed effects, and baseline body weight
value-by-visit interaction as a covariate.
[1334] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1335] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy.
[1336] Included are patients who have measurements at baseline and
post-baseline.
TABLE-US-00021 TABLE 14 Mean change in fasting plasma glucose
(mmol/L) from baseline to Week 30 using MMRM-mITT population (FIGS.
4 and 5) Fixed Ratio Insulin Fasting plasma Combination Glargine
Lixisenatide glucose (mmol/L) (N = 468) (N = 466) (N = 233)
Baseline Number 465 465 232 Mean (SD) 9.88 (2.34) 9.75 (2.33) 9.79
(2.16) Median 9.70 9.30 9.70 Min:Max 4.3:17.8 4.7:21.5 5.5:19.4
Week 30 Number 436 438 216 Mean (SD) 6.32 (1.47) 6.53 (1.76) 8.27
(2.24) Median 6.00 6.20 8.00 Min:Max 3.1:14.3 3.3:15.9 3.2:24.4
Change from baseline to Week 30 Number 465 465 232 LS Mean
(SE).sup.a -3.46 (0.090) -3.27 (0.091) -1.50 (0.124) LS mean -0.19
(0.117) -- -- difference (SE) vs insulin glargine.sup.a 95% Cl
(-0.420 to 0.038) -- -- p-value 0.1017 -- -- LS mean -1.96 (0.144)
-- -- difference (SE) vs lixisenatide.sup.a 95% Cl (-2.246 to
-1.682) -- -- p-value <0.0001 -- -- .sup.aMixed-effect model
with repeate measures (MMRM) with treatment groups (fixed ratio
combination, insulin glargine alone, lixisenatide alone),
randomization strata of HbA1c (<8.0%, .gtoreq.8.0%) at Visit 4
(Week -1), randomization strata of second OAD use at screening
(Yes, No), scheduled visit, treatment-by-visit interaction and
country as fixed effects, and baseline fasting plasma glucose
value-by-visit interaction as a covariate.
[1337] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1338] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy.
[1339] Included are patients who have measurements at baseline and
post-baseline.
TABLE-US-00022 TABLE 15 Mean change in average 7-point SMPG
(mmol/L) from baseline to Week 30 using MMRM-mITT population (FIG.
6) Average Fixed Ratio Insulin of 7-point Combination Glargine
Lixisenatide SMPG (mmol/L) (N = 468) (N = 466) (N = 233) Baseline
Number 421 411 204 Mean (SD) 10.47 (2.15) 10.31 (2.15) 10.41 (2.01)
Median 10.03 10.07 10.33 Min:Max 5.2:16.8 5.8:18.3 6.0:17.2 Week 30
Number 382 368 184 Mean (SD) 7.09 (1.25) 7.75 (1.49) 8.54 (1.79)
Median 6.90 7.49 8.42 Min:Max 4.9:13.6 5.0:15.5 5.4:18.1 Change
from baseline to Week 30 Number 421 411 204 LS Mean (SE).sup.a
-3.35 (0.081) -2.66 (0.084) -1.95 (0.111) LS mean -0.69 (0.101) --
-- difference (SE) vs insulin glargine.sup.a 95% Cl (-0.892 to
-0.495) -- -- p-value <0.0001 -- -- LS mean -1.40 (0.124) -- --
difference (SE) vs lixisenatide.sup.a 95% Cl (-1.645 to -1.158) --
-- p-value <0.0001 -- -- SMPG = Self-monitored plasma glucose.
.sup.aMixed-effect model with repeated measures (MMRM) with
treatment groups (fixed ratio combination, insulin glargine alone,
lixisenatide alone), randomization strata of HbA1c (<8.0%,
.gtoreq.8.0%) at Visit 4 (Week -1), randomization strata of second
OAD use at screening (Yes, No), scheduled visit, treatment-by-visit
interaction and country as fixed effects, and baseline average SMPG
value-by-visit interaction as a covariate.
[1340] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1341] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy.
[1342] Included are patients who have measurements at baseline and
post-baseline.
TABLE-US-00023 TABLE 16 Number (%) of patients reaching HbA1c
<7.0% with no body weight gain at Week 30-mITT population Fixed
Ratio Insulin HbA1c <7% with no Combination Glargine
Lixisenatide body weight gain (N = 468) (N = 466) (N = 233) Number
468 466 233 Yes 202 (43.2%) 117 (25.1%) 65 (27.9%) Proportion
difference 18.08% (12.15% -- -- (95% Cl) vs. to insulin
glargine.sup.a 24.01%) p-value <.0001 -- -- Proportion
difference 15.22% (8.05% -- -- (95% Cl) vs. to lixisenatide.sup.a
22.39%) .sup.aWeighted average of proportion difference between
treatment groups (fixed ratio combination, insulin glargine,
lixisenatide) from each strata (randomization strata of HbA1c
[<8.0, .gtoreq.8.0%] at Visit 4 (Week -1), randomization strata
of second OAD use at screening [Yes, No]) using
Cochran-Mantel-Haenszel (CMH) weights.
[1343] The analysis included HbA1c and body weight measurements at
week 30, including those obtained after the IMP discontinuation or
the introduction of rescue medication.
[1344] Patients were treated as non-responders if they have no
HbA1c and/or body weight assessments at week 30.
TABLE-US-00024 TABLE 17 Number (%) of patients reaching HbA1c
<7.0% with no body weight gain at Week 30 and with no documented
symptomatic hypoglycemia (plasma glucose concentration .ltoreq.70
mg/dL [3.9 mmol/L] during the study-mITT population HbA1c <7%
with no weight gain and with no documented Fixed Ratio Insulin
symptomatic Combination Glargine Lixisenatide hypoglycemia (N =
468) (N = 466) (N = 233) Number 468 466 233 Yes 149 (31.8%) 88
(18.9%) 61 (26.2%) Proportion 12.98% (7.50% -- -- difference to
(95% Cl) vs. 18.45%) insulin glargine.sup.a p-value <.0001 -- --
Proportion 5.61% (-1.33% -- -- difference to (95% Cl) vs. 12.55%)
lixisenatide.sup.a .sup.aWeighted average of proportion difference
between treatment groups (fixed ratio combination, insulin
glargine, lixisenatide) from each strata (randomization strata of
HbA1c [<8.0, .gtoreq.8.0%] at Visit 4 (Week -1), randomization
strata of second OAD use at screening [Yes, No]) using
Cochran-Mantel-Haenszel (CMH) weights.
[1345] Documented symptomatic hypoglycemia is an event during which
typical symptoms of hypoglycemia are accompanied by a measured
plasma glucose of 70 mg/dL (3.9 mmol/L).
[1346] The analysis included all HbA1c and body weight measurements
at week 30, including those obtained after the IMP discontinuation
or the introduction of rescue medication. Patients were treated as
non-responders if they have no HbA1c and/or body weight assessments
at week 30.
[1347] All documented symptomatic hypoglycemia occurred during the
30-week open-label treatment period was considered, including those
occurred after the IMP discontinuation or the introduction of
rescue medication.
TABLE-US-00025 TABLE 18 Average daily insulin glargine dose (U) at
Week 30 using MMRM--mITT population (FIG. 7) Fixed Ratio Insulin
Average daily insulin glargine Combination Glargine dose (U) (N =
468) (N = 466) Week 30 Number 438 440 Mean (SD) 39.75 (14.87) 40.34
(14.85) Median 40.00 40.00 Min:Max 10.0:60.0 4.0:62.0 Week 30
Number 467 463 LS Mean (SE).sup.a 39.77 (0.699) 40.46 (0.701) LS
mean difference (SE) vs -0.69 (0.990) -- insulin glargine.sup.a 95%
CI (-2.632 to 1.252) -- p-value 0.4857 -- .sup.aMixed-effect model
with repeated measures (MMRM) with treatment groups (fixed ratio
combination, insulin glargine), randomization strata of HbA1c
(<8.0%, .gtoreq.8.0%) at Visit 4 (Week -1), randomization strata
of second OAD use at screening (Yes, No), scheduled visit,
treatment-by-visit interaction, and country as fixed effects.
[1348] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1349] The analysis included scheduled measurements obtained up to
the date of last injection of the IMP, including those obtained
after introduction of rescue therapy.
3.3 Safety
[1350] Symptomatic hypoglycemia events were documented on a
specific hypoglycemia event form, and not an AE CRF page, and thus
were not included in the TEAE summaries. They are summarized
separately from TEAEs.
TABLE-US-00026 TABLE 19 Overview of adverse event profile:
treatment emergent adverse events--Safety population Fixed Ratio
Insulin Combination Glargine Lixisenatide n (%) (N = 469) (N = 467)
(N = 233) Patients with any TEAE 267 (56.9%) 227 157 (48.6%)
(67.4%) Patients with any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%)
Patients with any TEAE 267 (56.9%) 227 157 (48.6%) (67.4%) Patients
with any TEAE leading 12 (2.6%) 9 (1.9%) 21 (9.0%) to permanent
treatment discontinuation Patients with any TEAE leading 2 (0.4%) 3
(0.6%) 1 (0.4%) to death TEAE: Treatment Emergent Adverse Event. n
(%) = number and percentage of patients with at least one TEAE.
TABLE-US-00027 TABLE 20 Number (%) of patients experiencing TEAE(s)
(PT 3% in any treatment group) by primary SOC and PT--Safety
population Fixed Ratio Insulin Primary System Organ Class
Combination Glargine Lixisenatide Preferred Term n(%) (N = 469) (N
= 467) (N = 233) Any TEAE 267 (56.9%) 227 (48.6%) 157 (67.4%)
Infections and infestations 130 (27.7%) 126 (27.0%) 60 (25.8%)
Influenza 15 (3.2%) 11 (2.4%) 4 (1.7%) Nasopharyngitis 26 (5.5%) 25
(5.4%) 15 (6.4%) Upper respiratory tract infection 33 (7.0%) 23
(4.9%) 12 (5.2%) Nervous system disorders 50 (10.7%) 30 (6.4%) 31
(13.3%) Dizziness 16 (3.4%) 7 (1.5%) 7 (3.0%) Headache 24 (5.1%) 15
(3.2%) 18 (7.7%) Gastrointestinal disorders 102 (21.7%) 59 (12.6%)
86 (36.9%) Diarrhoea 42 (9.0%) 20 (4.3%) 21 (9.0%) Nausea 45 (9.6%)
17 (3.6%) 56 (24.0%) Any TEAE 267 (56.9%) 227 (48.6%) 157 (67.4%)
Vomiting 15 (3.2%) 7 (1.5%) 15 (6.4%) Musculoskeletal and
connective 51 (10.9%) 41 (8.8%) 29 (12.4%) tissue disorders Back
pain 16 (3.4%) 10 (2.1%) 8 (3.4%) TEAE: Treatment emergent adverse
event, SOC: System Organ Class, PT: Preferred Term. MedDRA 18.0 n
(%) = number and percentage of patients with at least one TEAE.
Note: Table sorted by SOC internationally agreed order and PT
alphabetic order. Only SOC with at least one PT .gtoreq. 3% in at
least one group are presented.
3.3.1 Deaths, Serious Treatment-Emergent Adverse Events
[1351] Six patients experienced at least 1 TEAE leading to death: 2
from the fixed ratio combination group, 3 from the insulin glargine
group and 1 from the lixisenatide group (Table 21). None of the
fatal events were considered related to the IMP by the
Investigator. [1352] Fixed ratio combination group: [1353] A 64
year-old male patient died of lung cancer metastatic. [1354] A 72
year-old male patient died of cardiac failure congestive. [1355]
Insulin glargine group: [1356] A 55 year-old male patient died from
acute myocardial infarction and acute pulmonary edema. [1357] A 62
year-old male patient died of cardiac failure acute. [1358] A 60
year-old male died about 3 months after the treatment period due to
the worsening of undifferentiated keratinized squamous cell
carcinoma in mouth (diagnosed during the on-treatment period).
[1359] Lixisenatide group: [1360] A 63 year-old female, was
reported to be found dead on her bed due to unknown reasons 208
days after the first dose of the study drug. Autopsy was not
performed. No other information was provided. This case was
adjudicated by the CAC as CV Death.
TABLE-US-00028 [1360] TABLE 21 Number (%) of patients experiencing
TEAE(s) leading to death by primary SOC and PT--Safety population
Fixed Ratio Insulin Primary System Organ Class Combination Glargine
Lixisenatide Preferred Term [n (%)] (N = 469) (N = 467) (N = 233)
Any TEAE leading to death 2 (0.4%) 3 (0.6%) 1 (0.4%) Neoplasms
benign, malignant 1 (0.2%) 1 (0.2%) 0 and unspecified (incl cysts
and polyps) Lung cancer metastatic 1 (0.2%) 0 0 Squamous cell
carcinoma of 0 1 (0.2%) 0 the oral cavity Cardiac disorders 1
(0.2%) 2 (0.4%) 0 Acute myocardial infarction 0 1 (0.2%) 0 Cardiac
failure acute 0 1 (0.2%) 0 Cardiac failure congestive 1 (0.2%) 0 0
Respiratory, thoracic and 0 1 (0.2%) 0 mediastinal disorders Acute
pulmonary oedema 0 1 (0.2%) 0 Any TEAE leading to death 2 (0.4%) 3
(0.6%) 1 (0.4%) General disorders and 0 0 1 (0.4%) administration
site conditions Death 0 0 1 (0.4%) TEAE: Treatment Emergent Adverse
Event, SOC: System Organ Class, PT: Preferred Term. MedDRA 18.0 n
(%) = number and percentage of patients with at least one TEAE
leading to death. Note: Table sorted by SOC internationally agreed
order and PT alphabetic order.
TABLE-US-00029 TABLE 22 Number (%) of patients experiencing serious
TEAE(s) presented by primary SOC and PT--Safety population Fixed
Ratio Insulin Primary System Organ Class Combination Glargine
Lixisenatide Preferred Term [n (%)] (N = 469) (N = 467) (N = 233)
Any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Infections and
infestations 4 (0.9%) 2 (0.4%) 2 (0.9%) Bronchitis 0 1 (0.2%) 0
Erysipelas 1 (0.2%) 0 1 (0.4%) Febrile infection 1 (0.2%) 0 0
Meningitis staphylococcal 0 0 1 (0.4%) Pneumonia 0 1 (0.2%) 0
Pyelonephritis acute 0 1 (0.2%) 0 Urinary tract infection 2 (0.4%)
0 0 Urosepsis 0 1 (0.2%) 0 Any serious TEAE 18 (3.8%) 19 (4.1%) 9
(3.9%) Neoplasms benign, malignant 2 (0.4%) 4 (0.9%) 1 (0.4%) and
unspecified (incl cysts and polyps) Lung cancer metastatic 1 (0.2%)
0 0 Lung neoplasm malignant 0 0 1 (0.4%) Metastases to liver 0 0 1
(0.4%) Pancreatic carcinoma 0 1 (0.2%) 0 Prostate cancer recurrent
0 1 (0.2%) 0 Squamous cell carcinoma of skin 1 (0.2%) 0 0 Squamous
cell carcinoma of the 0 1 (0.2%) 0 oral cavity Thyroid adenoma 0 1
(0.2%) 0 Blood and lymphatic system 0 1 (0.2%) 0 disorders
Pancytopenia 0 1 (0.2%) 0 Immune system disorders 0 0 1 (0.4%)
Anaphylactic reaction 0 0 1 (0.4%) Metabolism and nutrition 0 0 2
(0.9%) disorders Diabetes mellitus inadequate 0 0 1 (0.4%) control
Metabolic acidosis 0 0 1 (0.4%) Nervous system disorders 1 (0.2%) 1
(0.2%) 2 (0.9%) Lacunar infarction 0 1 (0.2%) 0 Radiculopathy 0 0 1
(0.4%) Transient ischaemic attack 1 (0.2%) 0 1 (0.4%) Any serious
TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Cardiac disorders 2 (0.4%) 6
(1.3%) 0 Acute myocardial infarction 0 1 (0.2%) 0 Cardiac failure
acute 0 1 (0.2%) 0 Cardiac failure chronic 0 1 (0.2%) 0 Cardiac
failure congestive 1 (0.2%) 1 (0.2%) 0 Coronary artery disease 0 1
(0.2%) 0 Myocardial infarction 0 1 (0.2%) 0 Palpitations 1 (0.2%) 0
0 Vascular disorders 1 (0.2%) 1 (0.2%) 0 Hypertension 1 (0.2%) 1
(0.2%) 0 Respiratory, thoracic and 0 3 (0.6%) 1 (0.4%) mediastinal
disorders Acute pulmonary oedema 0 1 (0.2%) 0 Chronic obstructive
pulmonary 0 1 (0.2%) 0 disease Dyspnoea 0 1 (0.2%) 0 Respiratory
failure 0 0 1 (0.4%) Gastrointestinal disorders 1 (0.2%) 0 0
Oesophagitis 1 (0.2%) 0 0 Hepatobiliary disorders 1 (0.2%) 0 0
Cholecystitis chronic 1 (0.2%) 0 0 Skin and subcutaneous tissue 2
(0.4%) 0 0 disorders Angioedema 1 (0.2%) 0 0 Urticaria 1 (0.2%) 0 0
Any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Musculoskeletal and
connective 0 1 (0.2%) 1 (0.4%) tissue disorders Costochondritis 0 1
(0.2%) 0 Spinal osteoarthritis 0 0 1 (0.4%) Renal and urinary
disorders 1 (0.2%) 2 (0.4%) 1 (0.4%) Acute kidney injury 0 0 1
(0.4%) Bladder prolapse 0 1 (0.2%) 0 Calculus urinary 0 1 (0.2%) 0
Hydronephrosis 0 1 (0.2%) 0 Renal colic 1 (0.2%) 0 0 Reproductive
system and breast 3 (0.6%) 0 0 disorders Acquired phimosis 1 (0.2%)
0 0 Cervical dysplasia 1 (0.2%) 0 0 Metrorrhagia 1 (0.2%) 0 0
General disorders and 0 1 (0.2%) 1 (0.4%) administration site
conditions Death 0 0 1 (0.4%) Non-cardiac chest pain 0 1 (0.2%) 0
Investigations 1 (0.2%) 1 (0.2%) 0 Electrocardiogram ST-T segment 1
(0.2%) 0 0 abnormal Lipase increased 0 1 (0.2%) 0 Any serious TEAE
18 (3.8%) 19 (4.1%) 9 (3.9%) Injury, poisoning and procedural 1
(0.2%) 1 (0.2%) 1 (0.4%) complications Comminuted fracture 0 1
(0.2%) 0 Tendon rupture 1 (0.2%) 0 0 Toxicity to various agents 0 0
1 (0.4%) TEAE: Treatment Emergent Adverse Event, SOC: System Organ
Class, PT: Preferred Term. MedDRA 18.0 n (%) = number and
percentage of patients with at least one serious TEAE. Note: Table
sorted by SOC internationally agreed order and PT alphabetic
order.
3.3.2 Adverse Events Leading to Withdrawal
TABLE-US-00030 [1361] TABLE 23 Number (%) of patients experiencing
TEAE(s) leading to permanent treatment discontinuation by primary
SOC and PT--Safety population Fixed Ratio Insulin Primary System
Organ Class Combination Glargine Lixisenatide Preferred Term [n
(%)] (N = 469) (N = 467) (N = 233) Any TEAE leading to permanent 12
(2.6%) 9 (1.9%) 21 (9.0%) treatment discontinuation Infections and
infestations 1 (0.2%) 1 (0.2%) 1 (0.4%) Bacteraemia 0 0 1 (0.4%)
Bronchitis 0 1 (0.2%) 0 Extradural abscess 0 0 1 (0.4%) Meningitis
staphylococcal 0 0 1 (0.4%) Urinary tract infection 1 (0.2%) 0 0
Any TEAE leading to permanent 12 (2.6%) 9 (1.9%) 21 (9.0%)
treatment discontinuation Neoplasms benign, malignant 1 (0.2%) 1
(0.2%) 1 (0.4%) and unspecified (incl cysts and polyps) Lung cancer
metastatic 1 (0.2%) 0 0 Lung neoplasm malignant 0 0 1 (0.4%)
Pancreatic carcinoma 0 1 (0.2%) 0 Immune system disorders 0 1
(0.2%) 1 (0.4%) Anaphylactic reaction 0 0 1 (0.4%) Drug
hypersensitivity 0 1 (0.2%) 0 Metabolism and nutrition 0 0 1 (0.4%)
disorders Decreased appetite 0 0 1 (0.4%) Psychiatric disorders 1
(0.2%) 1 (0.2%) 0 Depression 0 1 (0.2%) 0 Insomnia 1 (0.2%) 0 0
Nervous system disorders 0 1 (0.2%) 1 (0.4%) Diabetic
mononeuropathy 0 0 1 (0.4%) Headache 0 1 (0.2%) 1 (0.4%) Cardiac
disorders 1 (0.2%) 3 (0.6%) 1 (0.4%) Acute myocardial infarction 0
1 (0.2%) 0 Atrial fibrillation 0 0 1 (0.4%) Cardiac failure acute 0
1 (0.2%) 0 Cardiac failure congestive 1 (0.2%) 0 0 Any TEAE leading
to permanent 12 (2.6%) 9 (1.9%) 21 (9.0%) treatment discontinuation
Myocardial infarction 0 1 (0.2%) 0 Respiratory, thoracic and 0 2
(0.4%) 0 mediastinal disorders Acute pulmonary oedema 0 1 (0.2%) 0
Cough 0 1 (0.2%) 0 Gastrointestinal disorders 4 (0.9%) 1 (0.2%) 12
(5.2%) Abdominal distension 0 0 1 (0.4%) Abdominal pain 0 0 1
(0.4%) Colitis 0 0 1 (0.4%) Diarrhoea 1 (0.2%) 0 2 (0.9%) Dyspepsia
0 1 (0.2%) 0 Gastritis erosive 0 0 1 (0.4%) Nausea 2 (0.4%) 0 6
(2.6%) Vomiting 2 (0.4%) 0 4 (1.7%) Skin and subcutaneous tissue 4
(0.9%) 1 (0.2%) 1 (0.4%) disorders Rash 0 1 (0.2%) 0 Skin burning
sensation 1 (0.2%) 0 0 Urticaria 3 (0.6%) 0 1 (0.4%)
Musculoskeletal and connective 1 (0.2%) 0 0 tissue disorders Back
pain 1 (0.2%) 0 0 Any TEAE leading to permanent 12 (2.6%) 9 (1.9%)
21 (9.0%) treatment discontinuation General disorders and 0 1
(0.2%) 2 (0.9%) administration site conditions Death 0 0 1 (0.4%)
Fatigue 0 1 (0.2%) 0 Injection site erythema 0 0 1 (0.4%)
Investigations 0 1 (0.2%) 2 (0.9%) Alanine aminotransferase 0 0 1
(0.4%) increased Blood creatinine increased 0 0 1 (0.4%) Lipase
increased 0 1 (0.2%) 0 Injury, poisoning and procedural 0 1 (0.2%)
0 complications Comminuted fracture 0 1 (0.2%) 0 TEAE: Treatment
Emergent Adverse Event, SOC: System Organ Class, PT: Preferred
Term. MedDRA 18.0 n (%) = number and percentage of patients with at
least one TEAE leading to permanent treatment discontinuation.
Note: Table sorted by SOC internationally agreed order and PT
alphabetic order.
TABLE-US-00031 TABLE 24 Number (%) of patients experiencing
injection site reactions during the on-treatment period--Safety
population Fixed Ratio Insulin Event source Combination Glargine
Lixisenatide Preferred Term (N = 469) (N = 467) (N = 233) Any
injection site reactions 12 (2.6%) 8 (1.7%) 7 (3.0%) PTs coded from
the investigator 12 (2.6%) 8 (1.7%) 7 (3.0%) reported terms
Injection site bruising 4 (0.9%) 4 (0.9%) 0 Injection site pain 2
(0.4%) 2 (0.4%) 3 (1.3%) Injection site reaction 2 (0.4%) 1 (0.2%)
2 (0.9%) Injection site discomfort 1 (0.2%) 0 0 Injection site
irritation 1 (0.2%) 0 0 Injection site nodule 1 (0.2%) 0 0
Injection site papule 1 (0.2%) 0 0 Injection site rash 1 (0.2%) 0 0
Injection site erythema 0 0 2 (0.9%) Injection site haemorrhage 0 2
(0.4%) 0 Injection site swelling 0 1 (0.2%) 0 Injection site warmth
0 1 (0.2%) 0 PTs coded from the ARAC 2 (0.4%) 0 2 (0.9%) diagnosis
terms Injection site reaction 2 (0.4%) 0 2 (0.9%) ARAC = Allergic
Reaction Assessment Committee, PT = Preferred term.
[1362] One case of injection site erythema reported in the
lixisenatide group led to treatment discontinuation. A 56-year old
female patient developed erythema at the site of the lixisenatide
injection (abdomen and anterior regions of the thighs), accompanied
by local swelling and itching. Injection site erythema of mild
intensity was diagnosed, and subsequently the patient permanently
discontinued IMP. No corrective treatment was given and the patient
recovered without sequelae. The Investigator considered the event
to be related to IMP.
TABLE-US-00032 TABLE 25 Number (%) of patients with events
adjudicated as allergic reaction by ARAC during the on-treatment
period--Safety population Relationship MedDRA Coded to Study ARAC
Term (PT) Fixed Ratio Insulin Treatment Diagnosis for ARAC
Combination Glargine Lixisenatide (by ARAC) Categories Diagnosis (N
= 469) (N = 467) (N = 233) All Any category Any event 6 (1.3%) 3
(0.6%) 2 (0.9%) Urticaria (hives) Urticaria 3 (0.6%) 1 (0.2%) 1
(0.4%) Angioedema Angioedema 3 (0.6%) 0 0 Anaphylactic Anaphylactic
0 0 1 (0.4%) reaction reaction Other allergic Conjunctivitis 0 1
(0.2%) 0 reaction allergic Rhinitis allergic 0 2 (0.4%) 0 Possibly
Any category Any event 3 (0.6%) 0 2 (0.9%) related to Urticaria
(hives) Urticaria 3 (0.6%) 0 1 (0.4%) IMP Anaphylactic Anaphylactic
0 0 1 (0.4%) reaction reaction Not related Any category Any event 3
(0.6%) 3 (0.6%) 0 to IMP Urticaria (hives) Urticaria 0 1 (0.2%) 0
Angioedema Angioedema 3 (0.6%) 0 0 Other allergic Conjunctivitis 0
1 (0.2%) 0 reaction allergic Rhinitis allergic 0 2 (0.4%) 0 ARAC =
Allergic Reaction Assessment Committee, IMP = Investigational
medicinal product.
[1363] One allergic event adjudicated as anaphylactic reaction by
the ARAC was reported in the lixisenatide group and occurred in a
60 year-old female patient 1 hour after IMP administration. The
patient developed generalized itching, skin eruption, hand and face
edema, and wheezing. She was taken to the emergency room and
recovered following intramuscular dexamethasone.
TABLE-US-00033 TABLE 26 Number (%) of patients with pancreatic
events positively adjudicated by PSAC during the on-treatment
period--Safety population Fixed Ratio Insulin Combination Glargine
Lixisenatide (N = 469) (N = 467) (N = 233) Any with "Yes" for
pancreatitis 0 0 0 by PSAC Acute pancreatitis 0 0 0 Acute on
chronic pancreatitis 0 0 0 Chronic pancreatitis 0 0 0 Unknown
pancreatitis 0 0 0 PSAC = Pancreatic Safety Assessment Committee.
Note: The on-treatment period is defined as the time from the first
injection of IMP up to 3 days after the last injection of IMP,
regardless of the introduction of rescue therapy.
[1364] One case of pancreatic cancer was reported in the insulin
glargine group. A 75 year-old male patient was diagnosed with
pancreatic carcinoma and permanently discontinued insulin glargine.
Two months afterwards the patient died of gastrointestinal
hemorrhage. The patient had a history of peptic ulcer disease. This
fatal event was considered not to be possibly related to IMP by the
Investigator. The case was adjudicated by PSAC as pancreatic
carcinoma not related to IMP.
TABLE-US-00034 TABLE 27 Number (%) of patients with events
adjudicated as major cardiovascular events by CAC during the
on-treatment period--Safety population Fixed Ratio Insulin
Combination Glargine Lixisenatide n(%) (N = 469) (N = 467) (N =
233) Any 2 (0.4%) 7 (1.5%) 2 (0.9%) Cardiovascular death 1 (0.2%) 2
(0.4%) 1 (0.4%) Non-fatal myocardial infarction 0 0 0 Non-fatal
stroke 0 1 (0.2%) 1 (0.4%) Hospitalization for unstable 1 (0.2%) 1
(0.2%) 0 angina Hospitalization for heart failure 0 2 (0.4%) 0
Coronary revascularization 0 1 (0.2%) 0 procedure CAC =
Cardiovascular Events Adjudication Committee n (%) = number and
percentage of patients with events adjudicated as major
cardiovascular events by CAC.
TABLE-US-00035 TABLE 28 Number (%) of patients with events reported
on the AE form for increased calcitonin (.gtoreq.20 ng/L) during
the on-treatment period--Safety population Fixed Ratio Insulin
Combination Glargine Lixisenatide Preferred Term (N = 469) (N =
467) (N = 233) Any 0 1 (0.2%) 0 Blood calcitonin increased 0 1
(0.2%) 0 n (%) = number and percentage of patients with any cases
reported on the AE form for increased calcitonin .gtoreq.20 pg/mL
along with complementary form.
TABLE-US-00036 TABLE 29 Number (%) of patients with events reported
on the AE form for ALT increase during the on-treatment
period--Safety population Fixed Ratio Insulin Combination Glargine
Lixisenatide Preferred Term (N = 469) (N = 467) (N = 233) Any 1
(0.2%) 2 (0.4%) 1 (0.4%) Any 1 (0.2%) 2 (0.4%) 1 (0.4%) Alanine
aminotransferase 1 (0.2%) 2 (0.4%) 1 (0.4%) increased n (%) =
number and percentage of patients with any cases reported on the AE
form for ALT increase along with complementary form.
TABLE-US-00037 TABLE 30 Number (%) of patients with events reported
in pen-related event questionnaire during the on-treatment
period--Safety population Fixed Ratio Insulin Combination Glargine
Lixisenatide (N = 469) (N = 467) (N = 233) Any pen-related events
25 (5.3%) 10 (2.1%) 9 (3.9%) Associated with a clinical event 0 0 0
Not associated with a clinical event 25 (5.3%) 10 (2.1%) 9 (3.9%)
Clinical event = symptomatic hypoglycemic event, hyperglycemic
adverse event or other adverse event collected in pen-related
questionnaire.
3.3.3 Other Safety Observation--Symptomatic Hypoglycemia
TABLE-US-00038 [1365] TABLE 31 Summary of symptomatic hypoglycemia
recorded on the dedicated eCRF page and meeting protocol definition
during the on-treatment period--Safety population Fixed Ratio
Insulin Combination Glargine Lixisenatide (N = 469) (N = 467) (N =
233) Total patient years of exposure 263.1 262.5 125.2 Total
patient years of exposure 263.1 262.5 125.2 Symptomatic
hypoglycemia Number of patients with 128 (27.3%) 119 (25.5%) 15
(6.4%) events, n (%) Number of patients with events 0.49 0.45 0.12
per patient year .sup.a Number of events 409 338 46 Number of
events per patient 1.55 1.29 0.37 year .sup.b Documented
symptomatic hypoglycemia (plasma glucose .ltoreq.70 mg/dL [3.9
mmol/L]) Number of patients with 120 (25.6%) 110 (23.6%) 15 (6.4%)
events, n (%) Number of patients with events 0.46 0.42 0.12 per
patient year .sup.a Number of events 378 321 43 Number of events
per patient 1.44 1.22 0.34 year .sup.b Documented symptomatic
hypoglycemia (plasma glucose <60 mg/dL [3.3 mmol/L]) Number of
patients with 66 (14.1%) 50 (10.7%) 6 (2.6%) events, n (%) Number
of patients with events 0.25 0.19 0.05 per patient year .sup.a
Number of events 128 75 13 Number of events per patient 0.49 0.29
0.10 year .sup.b Probable symptomatic hypoglycemia Number of
patients with 17 (3.6%) 12 (2.6%) 2 (0.9%) events, n (%) Number of
patients with events 0.06 0.05 0.02 per patient year .sup.a Number
of events 31 16 3 Total patient years of exposure 263.1 262.5 125.2
Number of events per patient 0.12 0.06 0.02 year .sup.b Severe
symptomatic hypoglycemia Number of patients with 0 1 (0.2%) 0
events, n (%) Number of patients with events 0 <0.01 0 per
patient year .sup.a Number of events 0 1 0 Number of events per
patient 0 <0.01 0 year .sup.b IMP: Investigational Medicinal
Product, eCRF: electronic Case Report Form. Patient years of
exposure: calculated as time from the first to the last injection
of IMP plus 1 day. .sup.a Calculated as number of patients with
events divided by total patient years of exposure.. .sup.b
Calculated as number of events divided by total patient years of
exposure. Symptomatic hypoglycemia = symptomatic hypoglycemia
recorded on the dedicated eCRF and meeting protocol definition for
severe, or documented, or probable symptomatic hypoglycemia.
[1366] On-treatment period is defined as the time from the first
injection of IMP up to 1 day for symptomatic hypoglycemia after the
last injection of IMP, regardless of the introduction of rescue
therapy.
Example 3
[1367] A randomized, 30-week, active-controlled, open label,
2-treatment arm, parallel-group, multicenter study comparing the
efficacy and safety of the insulin glargine/lixisenatide fixed
ratio combination to insulin glargine with or without metformin in
patients with T2DM [1368] AE: Adverse event [1369] ALT: Alanine
aminotransferase [1370] ARAC: Allergic Reaction Assessment
Committee [1371] ANCOVA: Analysis of covariance [1372] BMI: Body
mass index [1373] CAC: Cardiovascular Events Adjudication Committee
[1374] CI: Confidence interval [1375] CMH: Cochran-Mantel-Haenszel
[1376] ECG: Electrocardiogram [1377] FPG: Fasting plasma glucose
[1378] GFR: Glomerular filtration rate [1379] GLP-1: Glucagon-like
peptide-1 [1380] HbA1 Glycosylated hemoglobin [1381] cIMP:
Investigational medicinal product [1382] LOCF: Last observation
carried forward [1383] LS: Least squares [1384] mITT: Modified
Intent-To-Treat [1385] OAD: Oral anti-diabetic drug [1386] PG:
Plasma glucose [1387] PPG: Post-prandial plasma glucose [1388]
PSAC: Pancreas Safety Assessment Committee [1389] PT: Preferred
term [1390] SAE: Serious adverse event [1391] SD: Standard
deviation [1392] SMPG: Self-monitored plasma glucose [1393] SOC:
System orgn class [1394] TEAE: Treatment-emergent adverse event
[1395] ULN Upper limit of normal
2 Synopsis
[1396] Title of the study: A randomized, 30-week,
active-controlled, open label, 2-treatment arm, parallel-group,
multicenter study comparing the efficacy and safety of the insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
with or without metformin in patients with T2DM
Study center(s): Multicenter (236 centers in 18 countries) Phase of
development: Phase 3
Objectives:
Primary Objective
[1397] To demonstrate the superiority of the insulin
glargine/lixisenatide fixed ratio combination to insulin glargine
in HbA1c change from baseline to Week 30.
Secondary Objective(s)
[1398] To assess the effects of the insulin glargine/lixisenatide
fixed ratio combination in comparison with insulin glargine over 30
weeks on: [1399] Percentage of patients reaching HbA1c targets,
[1400] Glycemic control in relation to a meal as evaluated by
2-hour post-prandial plasma glucose (PPG) and glucose excursion
during a standardized meal test, [1401] Body weight, [1402] 7-point
self-monitored plasma glucose (SMPG) profile, [1403] Percentage of
patients reaching HbA1c targets with no body weight gain and/or
documented symptomatic hypoglycemia, [1404] Insulin glargine dose,
[1405] Fasting plasma glucose (FPG).
[1406] To assess the safety and tolerability in each treatment
group.
[1407] Methodology: This was an open-label, 1:1 randomized,
active-controlled, 2-arm, 30-week treatment duration,
parallel-group multinational and multicenter study. The
randomization was stratified by value of HbA1cat Visit 5 (Week -1)
(<8%, .gtoreq.8%) and metformin use at screening (Y, N).
[1408] The study comprised 3 periods: [1409] An up-to 8-week
screening period, which included an up to 2-week screening phase
and a 6-week run-in phase with switching to (if appropriate) and/or
titration/stabilization of insulin glargine dose, continuation of
metformin (if appropriate) and discontinuation of sulfonylurea(SU),
glinide, sodium-glucose co-transporter 2 inhibitor (SGLT-2i) or
dipeptidyl-peptidase-4 inhibitor (DPP-4i) if previously taken at
Visit 2 [1410] A 30-week open-label randomized treatment period
[1411] A 3-day post-treatment safety follow-up period
[1412] Number of patients: Planned: 700; [1413] Randomized: 736;
[1414] Treated: 730
[1415] Evaluated: Efficacy: 731 [1416] Safety: 730
[1417] Diagnosis and criteria for inclusion: Inclusion criteria:
Patients with type 2 diabetes mellitus diagnosed for at least 1
year and inadequately controlled on their current antidiabetic
treatment. Patients had to be treated with basal insulin for at
least 6 months at a stable daily dose of 15 to 40 U, alone or
combined with 1 or 2 oral anti-diabetic drugs ((metformin, an SU, a
glinide, a DPP-4 inhibitor, or a SGLT-2 inhibitor) at a stable dose
for at least 3 months. Key exclusion criteria for randomization (at
the end of the run-in phase): HbA1c<7% or >10% at Visit 5
(week-1); mean fasting SMPG>140 mg/dL (7.8 mmol/L) for the 7
days before the randomization Visit (Visit 6); average insulin
glargine daily dose<20 U or >50 U calculated for the last 3
days before Visit 6.
Study Treatments
[1418] Investigational medicinal product(s) (IMPs): Insulin
glargine/lixisenatide fixed ratio combination and insulin glargine
(Lantus.RTM.)
Formulation:
Test Drug: Insulin Glargine/Lixisenatide Fixed Ratio
Combination
[1419] Insulin glargine/lixisenatide fixed ratio combination
(hereafter referred to as fixed ratio combination) was supplied as
a sterile aqueous solution in a pre-filled disposable SoloStar.RTM.
pen-injector.
[1420] Two pens (A and B) with different fixed ratios were
available to allow insulin glargine titration over a range of 10 to
60 U/day while limiting the lixisenatide dose to a maximum of 20
g/day: [1421] Pen A contained 100 U/mL of insulin glargine and 50
.mu.g of lixisenatide in a ratio of 2:1 (2 units of insulin
glargine per 1 .mu.g lixisenatide). Doses could be set from 10 to
40 units in steps of 1 unit, allowing administration of daily
combination doses between 10 U/5 .mu.g and 40 U/20 .mu.g [1422] Pen
B contained 100 U/mL insulin glargine and 33 .mu.g/mL lixisenatide
in a ratio of 3:1. Doses could be set from 30 to 60 units in steps
of 1 unit, allowing administration of daily combination doses
between 30 U/10 .mu.g and 60 U/20 .mu.g.
[1423] The maximum daily dose was 60 units (60 U insulin glargine
and 20 .mu.g lixisenatide).
Control Drug: Insulin Glargine (Lantus.RTM.)
[1424] Insulin glargine was supplied as a sterile aqueous solution
in a pre-filled disposable SoloStar.RTM. pen-injector (100 U/mL
glargine). Doses could be set from 1 to 80 units in steps of 1
unit. However, in this study the maximum insulin glargine daily
dose allowed was 60 U.
Route of Administration: Subcutaneous Injection
Self-Administered
Dose Regimen:
During Run-in Phase
[1425] Starting from Visit 2, insulin glargine was the only basal
insulin allowed. Patients receiving any basal insulin other than
insulin glargine before screening switched to once daily insulin
glargine at Visit 2.1nsulin glargine was administered at any time
of the day and at around the same time every day. The injection
time was selected at the discretion of the patient and the
investigator at Visit 2 and was to remain the same throughout the
study (during the run-in phase for all patients and during the
randomized treatment period for patients randomized to insulin
glargine).
During the Open-Label Randomized Treatment Period
[1426] The combination treatment was injected once daily within the
house before breakfast. The starting dose was 20 U/10 .mu.g given
with Pen A if the insulin glargine dose on the day before
randomization was <30 U, and 30 U/10 .mu.g given with Pen B if
the insulin glargine dose on the day before randomization was 30 U.
The dose was kept stable for 2 weeks, then titrated once a week
based on the insulin glargine dose, to reach and maintain a target
fasting SMPG of 80 to 100 mg/dL [4.4 to 5.6 mmol/L] while avoiding
hypoglycemia episodes.
[1427] Patients randomized to insulin glargine started the
randomized treatment period with the same daily dose as that
received the day before randomization, with subsequent insulin dose
titration as necessary.
[1428] The same dose adjustment algorithm was recommended for
insulin glargine/lixisenatide fixed ratio combination and insulin
glargine.
[1429] Noninvestigational medicinal product(s): Background
treatment metformin (if taken) and rescue therapy were considered
as NIMP(s)
[1430] Metformin: tablets, administered orally. Dose regimen was in
accordance with locally approved label. If previously taken, was to
be continued at a stable dose throughout the study unless prevented
by a specific safety issue related to this treatment.
[1431] Other Oral anti-diabetic treatment: SUs, glinides, SGLT-2
inhibitors and DPP-4 inhibitors, if previously taken, were stopped
at the start of run-in (Visit 2).
Rescue Therapy:
[1432] Routine fasting SMPG and central lab alerts on FPG (and
HbA1c after Week 12) were set up to ensure that glycemic parameters
remained under predefined threshold values. If values were above
predefined thresholds, and no explanations were found, or
appropriate actions failed, or a dose>60 U was necessary to
decrease FPG and/or HbA1c below the threshold values, rescue
therapy was to be introduced along with IMP and metformin (if
taken). Newly initiated anti-diabetic medications, or an increase
from baseline in background metformin dose were considered as a
rescue therapy.
[1433] Duration of treatment: Up to 30 weeks
[1434] Duration of observation: Up to 39 weeks (up to 8-week
screening period+30-week randomized treatment period+3-day post
treatment safety follow-up)
Criteria for Evaluation:
[1435] Efficacy: [1436] Primary efficacy endpoint: Change in HbA1c
from baseline to Week 30. [1437] Secondary efficacy endpoints:
percent of patients with HbA1c<7% or 6.5% at Week 30, change
from baseline to Week 30 in 2-hour postprandial plasma glucose and
plasma glucose excursion, body weight, average 7-point SMPG;
percentage of patients reaching HbA1c<7% with no body weight
gain at Week 30 and/or with no documented (PG.ltoreq.70 mg/dL [3.9
mmol/L]) symptomatic hypoglycemia during the 30-week randomized
treatment period; change in daily dose of insulin glargine; change
in fasting plasma glucose; percentage of patients requiring rescue
therapy during the 30-week randomized treatment period.
Safety:
[1437] [1438] Symptomatic hypoglycemia [1439] Documented: typical
symptoms of hypoglycemia with a plasma glucose concentration 70
mg/dL (3.9 mmol/L) [1440] Probably: symptoms of hypoglycemia
without plasma glucose determination, but was presumably caused by
a plasma glucose concentration 70 mg/dL (3.9 mmol/L) [1441] Severe:
event requiring assistance of another person to actively administer
carbohydrate, glucagon, or other resuscitative actions [1442]
Treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs
leading to death, TEAEs leading to treatment discontinuation,
adverse events of special interest (EASIs) (i.e., increase in
alanine aminotransferase (ALT), pregnancy, symptomatic overdose
with IMP/NIMP), major cardiovascular events, potential allergic
reactions, pancreatic events (confirmed increased
amylase/lipase>2.times. upper limit of normal (ULN),
pancreatitis, pancreatic neoplasm, events of confirmed increased
calcitonin 20 pg/mL (5.9 pmol/L), pen-related events [1443] Safety
laboratory data (hematology, clinical chemistry, lipase/amylase and
calcitonin)
Statistical Methods:
[1444] Efficacy analysis was based on modified intent-to-treat
(mITT) population using efficacy assessment collected during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy. The mITT population consisted of
all randomized patients who had both a baseline assessment and at
least one post-baseline assessment of any primary or secondary
efficacy variables.
[1445] The primary efficacy endpoint was analyzed using a
mixed-effect model with repeated measures (MMRM). The MMRM model
included the treatment groups, randomization strata, visit,
treatment-by-visit interaction, and country as fixed-effect
factors, and the baseline HbA1c-by-visit interaction as covariate.
The adjusted mean change in HbA1c from baseline to Week 30 for each
treatment group was estimated in the framework of this model, as
well as the between-group difference and the 95% CI for the
adjusted mean.
[1446] Similar MMRM method or analysis of covariance (ANCOVA) was
applied on continuous secondary efficacy endpoints and the
Cochran-Mantei-Haenszel method stratified by randomization strata
was applied for categorical efficacy endpoints.
[1447] A step-down testing procedure was applied in order to
control the type 1 error. Once the primary endpoint was
statistically significant at the 5% 2-sided level, testing was
performed on selected secondary endpoints in the following order:
2-hour plasma glucose excursion, body weight, average 7-point SMPG,
percent of patients reaching HbA1c<7% with no body weight gain
at Week 30, daily dose of insulin glargine, percentage of patients
reaching HbA1c<7% with no body weight gain at Week 30 and with
no documented symptomatic hypoglycemia, and FPG. When an endpoint
was not statistically significant at the 5% level, subsequent tests
were not performed.
SUMMARY
[1448] Population characteristics: A total of 736 patients were
randomized to one of the two treatment groups (367 in the insulin
glargine/lixisenatide fixed ratio combination group, 369 in the
insulin glargine group).
[1449] A total of 731 randomized patients were included in the mITT
population for efficacy analyses and 730 randomized patients were
exposed to open-label treatment and included in the safety
population (Table 1). Demographics and baseline characteristics
were generally similar between the two treatment groups. The median
age was 60.0 years, the mean diabetes duration was about 12 years
and the mean BMI was about 31 kg/m.sup.2 at screening. The study
population was primarily Caucasian (91.7%), and 53.3% of the
population were female (Table 3).
Efficacy Results:
Primary Efficacy Endpoint:
[1450] The primary objective of the study was met as statistical
superiority of the fixed ratio combination over insulin glargine
was demonstrated in change in HbA1c from baseline to Week 30.
[1451] The least squared (LS) mean changes in HbA1c from baseline
to Week 30 were -1.13% for the fixed ratio combination group and
-0.62% for the insulin glargine group, reaching mean HbA1c levels
of 6.9% and 7.5% at Week 30, respectively.
[1452] Statistical superiority of the fixed ratio combination over
insulin glargine was demonstrated (LS mean difference=-0.52%, 95%
CI: -0.633% to -0.397%, p<0.0001) (Table 8).
Secondary Efficacy Endpoints:
[1453] At Week 30, significantly more patients treated with the
combination (54.9%) reached an HbA1c<7.0% compared to those
receiving insulin glargine (29.6%) with a difference of 25.5% and
p<0.0001. In addition, the percentage of patients reaching
HbA1c.ltoreq.6.5% was significantly higher in the combination group
(33.9%) than in the insulin glargine group (14.2%)
(difference=19.76%, p<0.0001) (Table 9).
[1454] Treatment with the combination significantly improved
postprandial glycemic control during a standardized liquid
breakfast meal in comparison to insulin glargine as shown by the
results for the mean change in 2-hour glucose excursion from
baseline to Week 30 (LS mean was -3.90 and -0.47 mmol/L,
respectively; difference=-3.43 mmol/L, p<0.0001) (Table 10). For
the 2-hour PPG assessment the LS mean change was -4.72 in the
combination group and -1.39 mmol/L in the insulin glargine group
with a difference of -3.33 mmol/L and 95% CI: -3.889 mmol/L to
-2.774 mmol/L(Table 11).
[1455] Body weight decreased in the combination group and increased
in the insulin glargine group with LS mean changes from baseline to
Week 30 of -0.67 kg and +0.70 kg, respectively. The difference
(-1.37 kg) between the two groups was statistically significant
(p<0.0001) (Table 12).
[1456] Patients treated with the combination had a statistically
significant greater decrease in average 7-point SMPG profiles
compared to patients treated with insulin glargine
(difference=-0.90 mmol/L, p<0.0001) (Table 13). Graphical
presentation of the 7-point SMPG profiles showed that values at all
time-points at Week 30 decreased from baseline in both treatment
groups. After 30 weeks of treatment, the 7-point SMPG profiles
showed that the values at all time-points were lower in the
combination group compared to the insulin glargine group (except
for the similar pre-breakfast values) (FIG. 12).
[1457] A significantly higher percentage of patients reached
HbA1c<7.0% with no body weight gain at Week 30 in the fixed
ratio combination group (34.2%) compared to the insulin glargine
group (13.4%) with a difference of 20.82% and p<0.0001 (Table
14). The percentage of patients reaching HbA1c<7.0% at Week 30
with no documented symptomatic hypoglycemia during the 30-week
treatment period was higher in the combination group (31.7%)
compared to the insulin glargine group (18.6%) (difference=13.22%,
95% CI: 7.12% to 19.32%) (Table 18). Moreover, more patients
reached HbA1c<7.0% with no body weight gain at Week 30 and with
no documented symptomatic hypoglycemia during the 30-week treatment
period in the combination group (19.9%) compared to the insulin
glargine group (9.0%) (difference=10.94%, 95% CI: 5.93% to 15.96%)
(Table 16).
[1458] A similar increase in the daily dose of insulin glargine
from baseline was observed in both treatment groups (10.64 U in the
combination group and 10.89 U in the insulin glargine group,
difference=-0.26 U, p=0.7362) with a similar mean daily dose at
Week 30 of about 47 U. (Table 15).
[1459] The LS mean reductions in FPG from baseline to Week 30 were
similar in the combination group (-0.35 mmol/L) and the insulin
glargine group (-0.46 mmol/L) (difference=0.11 mmol/L, 95% CI:
-0.207 to 0.428) (Table 17).
[1460] A total of 10 (2.7%) patients in the combination group and
22 (6.0%) patients in the insulin glargine group received rescue
therapy (difference=-3.35%, 95% CI: -6.33% to -0.36%) (Table
19).
Safety Results:
[1461] The fixed dose combination was overall well tolerated during
the 30-week on-treatment period; the safety profile of the
combination arm reflected those of its component parts.
[1462] A total of 195 (53.4%) patients in the combination group and
191 (52.3%) in the insulin glargine group reported
treatment-emergent adverse events (Table 20).
[1463] The most frequently reported TEAEs in the combination group
were nausea (10.4% versus 0.5% in the insulin glargine group), and
nasopharyngitis in the insulin glargine group (8.8% versus 8.8% in
the combination group). The incidence of gastrointestinal disorder
(System organ class) events was 17.0% in the combination group and
7.9% in the insulin glargine group, in which nausea: 10.4% versus
0.5%, vomiting: 3.6% versus 0.5% and diarrhoea: 4.4% versus 2.7%
were mainly reported in the corresponding groups. (Table 21).
[1464] Three patients experienced at least 1 TEAE leading to death:
1 from the combination group (PT: Pneumonia) and 2 from the insulin
glargine group (PTs: Gallbladder cancer and Cardiopulmonary
failure).
[1465] Serious TEAEs were reported by a similar proportion of
patients in each treatment group: 20 (5.5%) patients in the
combination group and 18 (4.9%) in the insulin glargine group
(Table 22). There were no Suspected Unexpected Serious Adverse
Reactions (SUSARs) reported in either group.
[1466] A higher number of patients withdrew from treatment due to
TEAEs in the combination group (10 [2.7%]) than from the insulin
glargine group (3 [0.8%]). The difference is mainly attributable to
the number of patients discontinuing due to nausea (4 [1.1%]
patients in the combination group versus none in the insulin
glargine group) (Table 23).
[1467] A total of 2 patients (none in the combination group and 2
patients the insulin glargine group) experienced injection site
reactions (Table 24). None of those reactions were considered
serious or severe or led to treatment discontinuation.
[1468] One event of allergic rhinitis reported in the insulin
glargine group was adjudicated by the Allergic Reaction Assessment
Committee (ARAC) as allergic reaction not related to the IMP. No
events in the combination group were adjudicated as an allergic
reaction by the ARAC.
[1469] (Table 25).
[1470] There were no cases of pancreatitis positively adjudicated
by the Pancreatic Safety Assessment Committee (PSAC). In addition,
no pancreatic neoplasms were reported in the study.
[1471] Five patients (1.4%) in the combination group and 4 patients
(1.1%) in the insulin glargine group reported events adjudicated as
major cardiovascular events by the Cardiovascular Events
Adjudication Committee (CAC) (Table 26).
[1472] Two patients in the insulin glargine group reported a TEAE
of increased calcitonin (20 pg/mL) versus none in the combination
group (Table 27).
[1473] One patient in the combination group and 2 patients in the
insulin glargine group experienced an AE of ALT increase during the
on-treatment period (Table 28). No event met the definition for
Hy's Law.
[1474] No symptomatic overdose with IMP was reported in either
treatment group during the on-treatment period.
[1475] There was one pregnancy (in the insulin glargine group)
reported during the treatment period with outcome of the pregnancy
not available yet.
[1476] A total of 26 patients (the combination: 11 [3.0%] and
insulin glargine: 15 [4.1%]) reported pen-related events in the
pen-related event questionnaire during the on-treatment period.
None was associated with a clinical event (i.e. symptomatic
hypoglycemic event, hyperglycemic adverse event or any other
adverse event) (Table 29).
[1477] Forty percent of the patients in the combination group and
42.5% of patients in the insulin glargine group reported at least
one event of documented (PG.ltoreq.70 mg/dL) symptomatic
hypoglycemia. The corresponding event rates per patient-year were
3.03 and 4.22, respectively.
[1478] Four patients (1.1%) in the combination group and 1 patient
(0.3%) in the insulin glargine group reported 5 and 1 events of
severe symptomatic hypoglycemia, respectively (Table 30). All
events of severe symptomatic hypoglycemia were also reported as
SAEs.
Preliminary Conclusions:
[1479] The primary objective of the study was met as the
statistical superiority of the fixed ratio combination over insulin
glargine in HbA1c change from baseline to Week 30 was demonstrated.
The fixed ratio combination with or without metformin for patients
not adequately controlled with basal insulin with or without OADs
significantly improved HbA1c, allowed more patients to reach HbA1c
treatment target, reduced 2-hour glucose excursions and 2-hour PPG,
average 7-point SMPG and body weight in comparison to insulin
glargine.
[1480] The fixed ratio combination was well tolerated with a safety
profile reflecting those of its component parts. Nausea was the
most frequently reported adverse event in the combination group.
The incidence of gastrointestinal TEAEs (nausea and vomiting) was
reported less frequently in this study compared to what is usually
reported with GLP-1 receptor agonists including lixisenatide. The
incidence of symptomatic hypoglycemia was similar in the
combination and insulin glargine treatment groups.
3 Results
3.1 Study Patients
3.1.1 Patient Accountability
[1481] Of the 1930 patients screened, 1018 (52.7%) entered the
6-week run-in period and 736 were randomized to one of the two
treatment groups (367 in the combination group and 369 in the
insulin glargine group) in 187 centers across 18 countries
(Australia, Canada, Chile, Czech Republic, Denmark, Estonia,
Hungary, Lithuania, Mexico, Netherlands, Poland, Romania, Russian
Federation, Slovakia, Spain, Sweden, Ukraine, and United States of
America). The main reason for screening failure was an HbA1c value
at the screening visit out of the protocol-defined range (458
[23.7%]).
[1482] A total of 731 randomized patients were included in the mITT
population for efficacy analyses, and 730 randomized patients were
exposed to open-label treatment and included in the safety
population (Table 1). Five randomized patients (1 in the
combination group and 4 in the insulin glargine) were not included
in the mITT population because they did not have any post baseline
efficacy data. Six patients were randomized but not treated: 5 of 6
patients were randomized by mistake as the patients were not
eligible for randomization and one patient withdrew informed
consent.
TABLE-US-00039 TABLE 1 Analysis populations - Randomized Population
Fixed Ratio Insulin Combination Glargine All Randomized population
367 (100%) 369 (100%) 736 (100%) Efficacy population Modified
Intent-to-Treat 366 (99.7%) 365 (98.9%) 731 (99.3%) (mITT) Safety
population 365 365 730 Note: The safety population patients are
tabulated according to treatment actually received (as treated).
For the efficacy population, patients are tabulated according to
their randomized treatment.
[1483] There is no patient randomized in a group and taking another
study treatment. There is no patient having switched their
treatment during the study.
3.1.2 Study Disposition
TABLE-US-00040 [1484] TABLE 2 Patient disposition - Randomized
population Fixed Ratio Insulin Combination Glargine (N = 367) (N=
369) Randomized and treated 365 (99.5%) 365 (98.9%) Completed the
open-label study 336 (91.6%) 355 (96.2%) treatment period Did not
complete the open-label 29 (7.9%) 10 (2.7%) study treatment period
Subject's request for treatment 19 (5.2%) 7 (1.9%) discontinuation
Reason for study treatment discontinuation Adverse event 12 (3.3%)
3 (0.8%) Lack of efficacy 0 0 Poor compliance to protocol 4 (1.1%)
1 (0.3%) Lost to follow-up 1 (0.3%) 0 Other reasons 12 (3.3%) 6
(1.6%) Status at last study contact Alive 366 (99.7%) 367 (99.5%)
Dead 1 (0.3%) 2 (0.5%) Lost to follow-up 0 0 Note: Percentages are
calculated using the number of patients randomized as
denominator.
3.1.3 Demographics and Baseline Characteristics
TABLE-US-00041 [1485] TABLE 3 Demographics and patient
characteristics at screening or baseline - Randomize population
Fixed Ratio Insulin Combination Glargine All (N = 367) (N = 369) (N
= 736) Age (years) Number 367 369 736 Mean (SD) 59.6 (9.4) 60.3
(87) 60.0 (9.1) Median 60.0 61.0 60.0 Min:Max 36:85 32:80 32:85 Age
group (years) [n (%)] Number 367 369 736 <50 50 (13.6%) 42
(11.4%) 92 (12.5%) .gtoreq.50 to <65 207 (56.4%) 207 (56.1%) 414
(56.3%) .gtoreq.65 to <75 89 (24.3%) 102 (27.6%) 191 (26.0%)
.gtoreq.7.5 21 (5.7%) 18 (4.9%) 39 (5.3%) Gender [n (%)] Number 367
369 736 Male 165 (45.0%) 179 (48.5%) 344 (46.7%) Female 202 (55.0%)
190 (51.5%) 392 (53.3%) Race [n (%)] Number 367 369 736
Caucasian/White 337 (91.8%) 338 (91.6%) 675 (91.7%) Black 17 (4.6%)
21 (5.7%) 38 (5.2%) Asian/Oriental 12 (3.3%) 8 (2.2%) 20 (2.7%)
Other 1 (0.3%) 2 (0.5%) 3 (0.4%) Ethnicity [n (%)] Number 367 369
736 Hispanic 66 (18.0%) 66 (17.9%) 132 (17.9%) Not Hispanic 301
(82.0%) 303 (82.1%) 604 (82.1%) HbA1c (%) at visit 1 (Week-8)
Number 367 369 736 Mean (SD) 8.51 (0.65) 8.54 (0.67) 8.53 (0.66)
Median 8.40 8.50 8.40 Min:Max 7.5:10.0 7.5:10.0 7.5:10.0 HbA1c (%)
at visit 5 (Week-1) Number 367 369 736 Mean (SD) 8.19 (0.64) 8.24
(0.71) 8.21 (0.68) Median 8.20 8.20 8.20 Min:Max 7.0:10.0 7.0:10.0
7.0:10.0 Randomization strata of HbA1c (%) at visit 5 (Week-1) [n
(%)] Number 367 369 <8 140 (38.1%) 142 (38.5%) 282 (38.3%)
.gtoreq.8 227 (61.9%) 227 (61.9%) 454 (61.7%) Randomization strata
of Metformin use at screening [n (%) ] Number 367 369 736 Yes 332
(90.5%) 331 (89.7%) 663 (90.1%) No 35 (9.5%) 38 (10.3%) 73 (9.9%)
Screening BMI (kg/m.sup.2) Number 367 369 736 Mean (SD) 31.46
(4.27) 31.08 (4.17) 31.27 (4.22) Median 31.31 30.76 30.99 Min:Max
20.4:40.0 20.3:40.0 20.3:40.0 Screening BMI categories (kg/m.sup.2)
[n (%) ] Number 367 369 736 <30 148 (40.3%) 157 (42.5%) 305
(41.4%) .gtoreq.30 219 (59.7%) 212 (57.5%) 431 (58.6%) Baseline BMI
(kg/m.sup.2) Number 367 369 736 Mean (SD) 31.33 (4.25) 30.96 (4.15)
31.14 (4.20) Median 31.18 30.62 30.86 Min:Max 21.2:40.8 20.5:41.5
20.5:41.5 Baseline BMI categories (kg/m.sup.2) [n (%) ] Number 367
369 736 <30 156 (42.5%) 158 (42.8%) 314 (42.7%) .gtoreq.30 211
(57.5%) 211 (57.2%) 422 (57.3%) BMI = Body Mass Index
TABLE-US-00042 TABLE 4 Disease characteristics at screening or
baseline - Randomized population Fixed Ratio Insulin Combination
Glargine All (N = 367) (N = 369) (N = 736) Duration of diabetes
(years) Number 367 368 735 Mean (SD) 12.02 (6.64) 12.13 (6.85)
12.08 (6.74) Median 10.49 11.32 10.75 Min:Max 1.1:36.7 1.0:42.7
1.0:41.7 Age at onset of Type 2 diabetes (years) Number 367 368 735
Mean (SD) 47.5 (9.6) 48.1 (9.0) 47.8 (9.3) Median 47.0 48.0 48.0
Min:Max 22:79 20:72 20:79 Duration of prior basal insulin treatment
(years) Number 367 369 736 Mean (SD) 3.12 (3.06) 3.31 (3.08) 3.22
(3.07) Median 2.15 2.29 2.20 Min:Max 0.4:20.6 0.2:24.8 0.2:24.8
Prior basal insulin use by type/regimen (Visit 2) Number 367 369
736 Insulin glargine 233 (63.5%) 241 (65.3%) 474 (64.4%) Insulin
detemir 48 (13.1%) 56 (15.2%) 104 14.1%) NPH 86 (23.4%) 72 (19.5%)
158 (21.5%) Daily dose of prior basal insulin (U) at run-in (Visit
2) Number 367 369 736 Mean (SD) 28.36 (8.22) 29.00 (8.14) 28.68
(8.18) Median 30.00 28.00 28.0 Min:Max 10.0:44.0 12.0:50.0
10.0:50.0 Average daily dose of insulin glargine (U) at
randomization (Visit 6).sup.a Number 366 369 735 Mean (SD) 35.04
(9.22) 35.23 (8.63) 35.13 (8.92) Median 35.00 36.00 36.00 Min:Max
15.0:58.0 12.0:52.0 12.0:58.0 Metformin use at screening recorded
in eCRF [n (%)] Number 367 369 736 Yes 329 (89.6%) 329 (89.2%) 658
(89.4%) No 38 (10.4%) 40 (10.8%) 78 (10.6%) Duration of metformin
treatment (years).sup.b Number 329 329 658 Mean (SD) 8.45 (5.48)
8.32 (5.62) 8.39 (5.55) Median 7.76 7.54 7.69 Min:Max 0.3:28.3
0.4:30.8 0.3:30.8 Daily dose of metformin at baseline (mg).sup.b
Number 329 329 658 Mean (SD) 2082.8 (499.2) 2042.0 (455.9) 2062.4
(478.1) Median 2000.0 2000.0 2000.0 Min:Max 850:3500 500:4000
500:4000 Categorized daily dose of metformin at baseline (mg)
[n(%)].sup.b Number 329 329 658 <1500 19 (5.8%) 10 (3.0%) 29
(4.4%) .gtoreq.1500-<2500 217 (66.0%) 244 (74.2%) 461 (70.1%)
.gtoreq.2500-<3000 57 (17.3%) 48 (14.6%) 105 (16.0%)
.gtoreq.3000 36 (10.9%) 27 (8.2%) 63 (9.6%) Number of OAD use at
screening [n (%)] Number 367 369 736 No OAD 18 (4.9%) 19 (5.1%) 37
(5.0%) 1 OAD 189 (51.5%) 210 (56.9%) 399 (54.2%) 2 OADs 160 (43.6%)
140 (37.9%) 300 (40.8%) OAD use by drug class at screening [n (%)]
Number 349 350 699 1 OAD 189 (51.5%) 210 (56.9%) 399 (54.2%)
Metformin only 170 (48.7%) 190 (54.3%) 360 (51.5%) Sulfonylurea
only 16 (4.6%) 14 (4.0%) 30 (4.3%) DPP-4 inhibitor only 2 (0.6%) 4
(1.1%) 6 (0.9%) SGLT-2 inhibitor only 0 1 (0.3%) 1 (0.1%) Glinide
only 1 (0.3%) 1 (0.3%) 2 (0.3%) Combination of 2 OADs 160 (43.6%)
140 (37.9%) 300 (40.8%) Metformin plus Sulfonylurea 137 (39.3%) 118
(33.7%) 255 (36.5%) Metformin plus DPP-4 inhibitor 20 (5.7%) 18
(5.1%) 38 (5.4%) Metformin plus Glinide 2 (0.6%) 3 (0.9%) 5 (0.7%)
Sulfonylurea plus DPP-4 inhibitor 1 (0.3%) 1 (0.3%) 2 (0.3%)
Duration of first OAD use (years).sup.c Number 349 350 699 Mean
(SD) 8.40 (5.51) 8.24 (5.64) 8.32 (5.57) Median 7.75 7.41 7.54
Min:Max 0.3:28.3 0.3:30.8 0.3:30.8 Duration of second OAD use
(years).sup.d Number 161 141 302 Mean (SD) 4.35 (3.53) 4.75 (4.95)
4.53 (4.25) Median 3.55 3.05 3.32 Min:Max 0.3:23.6 0.2:29.7
0.2:29.7 History of gestational diabetes [n (%)] Number 202 190 392
Yes (Female) 10 (5.0%) 10 (5.3%) 20 (5.1%) No (Female) 192 (95.0%)
180 (94.7%) 372 (94.9%) Prior use of GLP-1 receptor agonist [n (%)]
Number 367 369 736 Yes 29 (7.9%) 17 (4.6%) 46 (6.3%) No 338 (92.1%)
352 (95.4%) 690 (93.8%) Creatinine clearance at screening (mL/min)
Number 366 367 733 Mean (SD) 106.75 (32.32) 106.06 (31.08) 106.40
(31.69) Median 103.85 101.31 102.2 Min:Max 34.3:223.7 43.8:222.1
34.3:223.7 Creatinine clearance categories at screening (mL/min) [n
(%)] Number 366 367 733 <15 (end stage renal disease) 0 0 0
.gtoreq.15-<30 (severe decrease in GFR) 0 0 0 .gtoreq.30-<60
(moderate decrease in GFR) 18 (4.9%) 9 (2.5%) 27 (3.7%)
.gtoreq.60-<90 (mild decrease in GFR) 104 (28.4%) 117 (31.9%)
221 (30.2%) .gtoreq.90 (normal) 244 (66.7%) 241 (65.7%) 485 (66.2%)
.sup.aAveraged daily dose of insulin glargine recorded in eCRF for
the 3 days before randomization. .sup.bfor patients who took
metformin at screening; .sup.cfor patients who took OAD at
screening; .sup.dfor patients who took 2.sup.nd OAD at screening.
OAD = Oral anti-diabetic drug, SGLT-2 = Sodium glucose
co-transporter 2, DPP-4 = Dipeptidyl-peptidase 4, GLP-1 = Glucagon
like peptide-1, GFR = glomerular filtration rate.
[1486] Duration of first OAD is calculated based on eCFR History of
Diabetics page and derived as: (Date of informed consent--earliest
start date of OADs including metformin, sulfonylurea, glinide,
DPP-4, or SGLT-2+1)/365.25. Similarly, duration of second OAD is
based on the 2.sup.nd earliest start date of OADs recorded.
[1487] Creatinine clearance value is derived using the equation of
Cockcroft and Gault.
3.1.4 Dosage and Duration
TABLE-US-00043 [1488] TABLE 5 Exposure to investigational medicinal
product - Safety population Fixed Ratio Insulin Combination
Glargine (N = 365) (N = 365) Cumulative duration of treatment
exposure (patient years) 200.3 207.1 Duration of study treatment
(days) Number 363 363 Mean (SD) 201.5 (38.0) 208.4 (18.4) Median
211.0 210.0 Min:Max 1:242 12:224 Duration of study treatment by
category [n (%)] Missing duration 2 (0.5%) 2 (0.5%) 1-14 days 5
(1.4%) 1 (0.3%) 15-28 days 2 (05%) 1 (0.3%) 29-56 days 2 (0.5%) 0
57-84 days 6 (1.6%) 0 85-126 days 8 (2.2%) 3 (0.8%) 127-168 days 0
1 (0.3%) 169-210 days 153 (41.9%) 202 (55.3%) >210 days 187
(51.2%) 155 (42.5%) Cumulative duration of study treatment by
category [n (%)] Missing duration 2 (0.5%) 2 (0.5%) .gtoreq.1 day
363 (99.5%) 363 (99.5%) .gtoreq.15 days 358 (98.1%) 362 (99.2%)
.gtoreq.29 days 356 (97.5%) 361 (98.9%) .gtoreq.57 days 354 (97.0%)
361 (98.9%) .gtoreq.85 days 348 (95.3%) 361 (98.9%) .gtoreq.127
days 340 (93.2%) 398 (98.1%) .gtoreq.169 days 340 (93.2%) 357
(97.8%) .gtoreq.211 days 187 (51.2%) 155 (42.5%) IMP:
Investigational Medicinal Product Duration of exposure = (date of
the last open-label IMP injection - date of the first open-label
IMP injection) + 1. Note: Patients are considered in the treatment
group they actually received at randomization.
[1489] In the combination group, 1 patient (840539002) reported the
final insulin dose (in category of >40 U to 60 U) without kit
number and pen used. Therefore, pen information (pen A or pen B)
used at the end of treatment period was treated as missing (Table
6). For the same reason the final lixisenatide dose could not be
derived for this patient (Table 7).
TABLE-US-00044 TABLE 6 Number (%) of patients by final insulin dose
at the end of open-label treatment - Safety population Fixed Ratio
Insulin Combination Glargine Final Insulin Dose (N = 365) (N = 365)
<20 U 2 (0.5%) 3 (0.8%) .gtoreq.20 U to <30 U 44 (12.1%) 39
(10.7%) .gtoreq.30 U to .ltoreq.40 U 97 (26.6%) 87 (23.8%) >40 U
to .ltoreq.60 U 222 (60.8%) 236 (64.7%) >60 U 0 0 = 60 U 99
(27.1%) 112 (30.7%) Pen A .sup.a <20 U 2 (0.5%) .gtoreq.20 U to
<30 U 43 (11.8%) .gtoreq.30 U to .ltoreq.40 U 53 (14.5%) >40
U to .ltoreq.60 U 2 (0.5%) >60 U 0 Pen B .sup.b <20 U 0
.gtoreq.20 U to <30 U 1 (0.3%) .gtoreq.30 U to .ltoreq.40 U 44
(12.1%) >40 U to .ltoreq.60 U 219 (60.0%) >60 U 0 .sup.a 2U/1
.mu.g fixed ratio for insulin glargine/lixisenatide. .sup.b 3U/1
.mu.g fixed ratio for insulin glargine/lixisenatide. Note:
Percentages are calculated using the number of safety patients as
the denominator.
TABLE-US-00045 TABLE 7 Number (%) of patients by final lixisenatide
dose at the end of open-label treatment - Safety population Final
Fixed Ratio Lixisenatide Combination Dose (N = 365) <10 .mu.g 3
(0.8%) .gtoreq.10 .mu.g to <15 .mu.g 108 (29.6%) .gtoreq.15
.mu.g to .ltoreq.20 .mu.g 251 (68.8%) >20 .mu.g 2 (0.5%) Pen A
.sup.a <10 .mu.g 2 (0.5%) .gtoreq.10 .mu.g to <15 .mu.g 43
(11.8%) .gtoreq.15 .mu.g to .ltoreq.20 .mu.g 53 (14.5%) >20
.mu.g 2 (0.5%) Pen B .sup.b <10 .mu.g 1 (0.3%) .gtoreq.10 .mu.g
to <15 .mu.g 65 (17.8%) .gtoreq.15 .mu.g to .ltoreq.20 .mu.g 198
(54.2%) >20 .mu.g 0 .sup.a 2U/1 .mu.g fixed ratio for insulin
glargine/lixisenatide. .sup.b 3U/1 .mu.g fixed ratio for insulin
glargine/lixisenatide. Note: Percentages are calculated using the
number of safety patients as the denominator.
3.2 Efficacy
3.2.1 Primary Efficacy Endpoint
TABLE-US-00046 [1490] TABLE 8 Mean change in HbA1c (%) from
baseline to Week 30 using MMRM - mITT population Fixed Ratio
Insulin Combination Glargine HbA1c(%) (N = 366) (N = 365) Baseline
Number 364 364 Mean (SD) 8.07 (0.68) 8.08 (0.73) Median 8.00 8.00
Min:Max 6.6:10.2 5.9:10.0 Week 30 Number 346 355 Mean (SD) 6.94
(0.87) 7.48 (0.91) Median 6.80 7.40 Min:Max 5.0:9.8 5.6:11.2 Change
from baseline to Week 30 Number 364 364 LS Mean (SE).sup.a -1.13
(0.057) -0.62 (0.055) LS mean difference (SE) -0.52 (0.060) -- vs
insulin glargine.sup.a 95% CI (-0.633 to -0.397) -- p-value
<0.0001 -- .sup.aMixed-effect model with repeated measures
(MMRM) with treatment groups (fixed ratio combination and insulin
glargine), randomization strata of HbA1c (<8.0%, .gtoreq.8.0%)
at Visit 5 (Week -1), randomization strata of metformin use at
screening (Yes, No), visit (Week 8, 12, 24, and 30),
treatment-by-visit interaction, and country as fixed effects, and
baseline HbA1c value-by-visit interaction as covariates.
[1491] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1492] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy. Included are
patients who have measurements at baseline and post-baseline.
[1493] Mean HbA1c values (%) by visit and mean change of HbA1c (%)
from baseline by visit are shown in FIGS. 9 and 10
3.2.2 Other Key Efficacy Endpoints
TABLE-US-00047 [1494] TABLE 9 Number (%) of patients with HbAlc
value <=6.5% or <7% at Week 30 - mITT population Fixed Ratio
Insulin Combination Glargine HbA1c (%) (N = 366) (N = 365) Number
366 365 .gtoreq.6.5% 124 (33.9%) 52 (14.2%) Proportion difference
19.76% (13.90% to 25.62%) -- (95% CI) vs. insulin glargine.sup.a
p-value <.0001 -- <7% 201 (54.9%) 108 (29.6%) Proportion
difference 25.52% (18.94% to 32.10%) -- (95% CI) vs. insulin
glargine.sup.a p-value <.0001 -- .sup.aWeighted average of
proportion difference between treatment groups (fixed ratio
combination and insulin glargine) from each strata (randomization
strata of HbA1c [<8.0%, .gtoreq.8.0% ] at Visit 5 (Week -1),
randomization strata of metformin use at screening [Yes, No]) using
Cochran-Mantel-Haenszel (CHM) weights. Proportion difference =
difference of the proportions of patients achieving HbA1c value
.ltoreq.6.5% or <7%.
[1495] All measurements at week 30 were used, including those
obtained after IMP discontinuation or introduction of recue
therapy. If no assessment was available at week 30 at all, patients
were treated as non-responders.
TABLE-US-00048 TABLE 10 Mean change in 2-hour plasma glucose
excursion (mmol/L) during a standardized test from baseline to Week
30 using ANCOVA - mITT population 2-hour Fixed plasma glucose Ratio
Insulin excursion Combination Glargine (mmol/L) (N = 366) (N = 365)
Baseline Number 329 336 Mean (SD) 7.01 (3.47) 7.14 (3.11) Median
7.10 7.05 Min:Max -5.1:17.4 -1.1:17.7 Week 30 (LOCF) Number 329 336
Mean (SD) 3.11 (3.55) 6.71 (3.34) Median 2.90 6.40 Min:Max
-9.5:15.9 -5.7:16.7 Change from baseline to Week 30 (LOCF) Number
329 336 Mean (SD) -3.90 (4.17) -0.44 (3.34) Median -3.70 -0.30
Min:Max -18.2:9.8 -13.1:11.2 LS Mean (SE).sup.a -3.90 (0.285) -0.47
(0.274) LS mean -3.43 (0.251) -- difference (SE) vs insulin
glargine.sup.a 95% CI (-3.925 to -2.939) -- p-value <0.0001 --
LOCF = Last observation carried forward. .sup.aAnalysis of
covariance (ANCOVA) model with treatment groups (fixed ratio
combination and insulin glargine), randomization strata of HbA1c
(<8.0%, .gtoreq.8.0%) at Visit 5 (Week -1), randomization strata
of metformin use at screening (Yes, No), and country as fixed
effects and baseline 2-hour plasma glucose excursion value as a
covariate.
[1496] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1497] The analysis included measurements collected during the
study, including those obtained after IMP discontinuation or
introduction of recue therapy.
[1498] Patients with both baseline and Week 30 (LOCF) measurements
are included.
TABLE-US-00049 TABLE 11 Mean change in 2-hour postprandial plasma
glucose (mmol/L) during a standardized meal teat from baseline to
Week 30 using ANCOVA - mITT population Fixed Ratio Insulin 2-hour
postprandial Combination Glargine plasma glucose (mmol/L) (N = 366)
(N = 365) Baseline Number 332 340 Mean (SD) 14.85 (3.82) 14.97
(3.67) Median 14.75 14.80 Min:Max 3.5:25.9 4.9:27.5 Week 30 (LOCF)
Number 332 340 Mean (SD) 9.91 (3.90) 13.41 (3.83) Median 9.20 13.10
Min:Max 2.9:25.7 3.9:33.1 Change from baseline to Week 30 (LOCF)
Number 332 340 Mean (SD) -4.94 (4.49) -1.56 (4.20) Median -5.10
-1.50 Min:Max -17.7:11.5 -16.3:23.8 LS Mean (SE).sup.a -4.72
(0.322) -1.39 (0.310) LS mean difference (SE) -3.33 (0.284) -- vs
insulin glargine.sup.a 95% Cl (-3.889 to -2.774) -- LOCF = Last
observation carried forward. .sup.aAnalysis of covariance (ANCOVA)
model with treatment groups (fixed ratio combination and insulin
glargine), randomization strata of HbA1c (<8.0%, .gtoreq.8.0%)
at Visit 5 (Week -1), randomization strata of metformin use at
screening (Yes, No), and country as fixed effects and baseline
2-hour postprandial plasma glucose value as a covariate.
[1499] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1500] The analysis included measurements collected during the
study, including those obtained after IMP discontinuation or
introduction of rescue therapy.
[1501] Patients with both baseline and Week 30 (LOCF) measurements
are included.
TABLE-US-00050 TABLE 12 Mean change in body weight (kg) from
baseline to Week 30 using MMRM - mITT population Fixed Ratio
Insulin Combination Glargine Body Weight (kg) (N = 366) (N = 365)
Baseline Number 365 365 Mean (SD) 87.81 (14.42) 87.09 (14.75)
Median 88.00 84.90 Min:Max 44.3:127.5 44:8:135.6 Week 30 Number 348
357 Mean (SD) 87.48 (14.35) 87.96 (15.08) Median 87.00 85.90
Min:Max 43.5:127.9 45.7:137.0 Change from baseline to Week 30
Number 365 365 LS Mean (SE).sup.a -0.67 (0.181) 0.70 (0.178) LS
mean difference -1.37 (0.224) -- (SE) vs insulin glargine.sup.a 95%
CI (-1.808 to -0.30) -- p-value <0.0001 -- .sup.aMixed-effect
model with repeated measures (MMRM) with treatment groups (fixed
ratio combination and insulin glargine), randomization strata of
HbA1c (<8.0%, .gtoreq.8.0%) at Visit 5 (Week -1), randomization
strata of metformin use at screening (Yes, No), scheduled visit,
treatment-by-visit interaction and country as fixed effects, and
baseline body weight value-by-visit interaction as a covariate.
[1502] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1503] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy.
[1504] Included are patients who have measurements at baseline and
post-baseline.
[1505] Mean change in body weight from baseline by visit is shown
in FIG. 11.
TABLE-US-00051 TABLE 13 Mean change in average 7-point SMPG
(mmol/L) from baseline to Week 30 using MMRM mITT population Fixed
Ratio Insulin Average of 7-point Combination Glargine SMPG (mmol/L)
(N = 366) (N = 365) Baseline Number 323 320 Mean (SD) 9.22 (1.56)
9.05 (1.59) Median 9.14 8.96 Min:Max 5.3:13.8 49:15.7 Week 30
Number 301 305 Mean (SD) 7.75 (1.71) 8.62 (1.74) Median 7.40 8.26
Min:Max 4.7:14.3 5.1.16.3 Change from baseline to Week 30 Number
323 320 LS Mean (SE).sup.a -1.50 (0.137) -0.60 (0.130) LS mean
difference -0.90 (0.131) (SE) vs insulin glargine.sup.a 95% CI
(-1.154 to -0.640) -- p-value <0.0001 -- SMPG = Self-monitored
plasma glucose. .sup.aMixed-effect model with repeated measures
(MMRM) with treatment groups (fixed ratio combination and insulin
glargine), randomization strata oh HbA1c (<8.0%, .gtoreq.8.0%)
at Visit 5 (Week -1), randomization strata of metformin use at
screening (Yes, No), scheduled visit, treatment-by-visit
interaction and country as fixed effects, and baseline average SMPG
value-by-visit interaction as a covariate.
[1506] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1507] The analysis included all scheduled measurements obtained
during the study, including those obtained after IMP
discontinuation or introduction of rescue therapy. Included are
patients who have measurements at baseline and post-baseline.
[1508] FIG. 12 shows a plot of mean 7-point SMPG at baseline and
week 30.
TABLE-US-00052 TABLE 14 Number (%) of patients reaching HbA1c
<71% with no body weight gain at Week 30 - population Fixed
Ratio Insulin HbA1c <7% with no Combination Glargine body weight
gain (N = 366) (N = 365) Number 366 365 Yes 125 (34.2%) 49 (13.4%)
Proportion difference 20.82% (14.98% to 26.66%) -- (95% CI) vs.
insulin glargine.sup.a p-value <.0001 -- .sup.aWeighted average
of proportion difference between treatment groups (fixed ratio
combination and insulin glargine) from each strata (randomization
strata oh HbA1c [<8.0, .gtoreq.8.0%] at Visit 5 (Week -1),
randomization strata of metformin use at screening [Yes, No]) using
Cocharn-Mantel-Haenszel (CMH) weights.
[1509] The analysis included HbA1c and body weight measurements at
week 30, including those obtained after the UMP discontinuation or
the introduction of recue medication. Patients were treated as
on-responders if they have no HbA1c and/or body weight assessments
at week 30.
TABLE-US-00053 TABLE 15 Mean change in daily insulin glargine dose
(U) from baseline to Week 30 using MMI mITT population Fixed Ratio
Average daily insulin Combination Insulin Giargine glargine dose
(U) (N = 366) (N = 365) Baseline Number 364 365 Mean (SD) 34.98
(9.20) 35.23 (8.64) Median 34.50 36.00 Min:Max 15.0: 58.0 12.0:52.0
Week 30 Number 336 353 Mean (SD) 46.67 (12.64) 46.71 (12.49) Median
50.00 48.00 Min:Max 12.0:60.0 14.0:60.0 Change from baseline to
Week 30 Number 364 365 LS Mean (SE).sup.a 10.64 (0.001) 10.89
(0.587) LS mean difference (SE) -0.26 (0.766) -- vs insulin
glargine.sup.a 95% CI (-1.762 to 1.246) -- p-value 0.7362 --
.sup.aMixed-effect model with repeated measures (MMRM) with
treatment groups (fixed ratio combination and insulin glargine),
randomization strata of HbA1c (<8.0%, .gtoreq.8.0%) at Visit 5
(Week -1), randomization strata of metformin use at screening (Yes,
No), scheduled visit, treatment-by-visit interaction, and country
as fixed effects, and baseline daily insulin glargine dose-by-visit
interaction as a covariate.
[1510] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1511] The analysis included scheduled measurements obtained up to
the date of last injection of the IMP, including those obtained
after introduction of rescue therapy.
[1512] FIG. 13 shows a plot of mean daily insulin glargine dose by
visit.
[1513] Per the testing strategy for multiplicity adjustment which
is described in the protocol, the inferential testing for the two
following variables (the percentage of patients reaching
HbA1c<7.0% with no body weight gain at Week 30 and with no
documented symptomatic hypoglycemia, and FPG) was exploratory since
the analysis on daily dose of insulin glargine failed to show a
statistically significant difference.
TABLE-US-00054 TABLE 16 Number (%) of patients reaching HbA1c <
7% with no body weight gain at Week 30 and with no documented
(plasma glucose .ltoreq. 70 mg/dL [3.9 mmol/L]) symptomatic
hypoglycemia during the study-mITT population HbA1c < 7% with no
weight Fixed Ratio Insulin gain and with no documented Combination
Glargine symptomatic hypoglycemia (N = 366) (N = 365) Number 366
365 Yes 73 (19.9%) 33 (9.0%) Proportion difference (95% 10.94% --
CI) vs. insulin glargine.sup.a (5.93% to 15.96%) p-value <.0001
-- .sup.aWeighted average of proportion difference between
treatment groups (fixed ratio combination and insulin glargine)
from each strata (randomization strata of HbA1c [<8.0,
.gtoreq.8.0%] at Visit 5 (Week -1), randomization strata of
metformin use at screening [Yes, No]) using Cochran-Mantel-Haenszel
(CMH) weights.
[1514] Documented symptomatic hypoglycemia is an event during which
typical symptoms of hypoglycemia are accompanied by a measured
plasma glucose of 70 mg/dL (3.9 mmol/L).
[1515] The analysis included all HbA1c and body weight measurements
at week 30, including those obtained after the IMP discontinuation
or the introduction of rescue medication. Patients were treated as
non-responders if they have no HbA1c and/or body weight assessments
at week 30.
[1516] All documented symptomatic hypoglycemia occurred during the
30-week open-label treatment period was considered, including those
occurred after the UMP discontinuation or the introduction of recue
medication.
TABLE-US-00055 TABLE 17 Mean change in fasting plasma glucose
(mmol/L) from baseline to Week 30 using MMRM-mITT population Fixed
Ratio Insulin Fasting plasma Combination Glargine glucose (mmol/L)
(N = 366) (N = 365) Baseline Number 364 364 Mean (SD) 7.33 (1.94)
7.32 (2.07) Median 7.10 7.00 Min:Max 3.2:15.7 3.3:17.2 Week 30
Number 341 349 Mean (SD) 6.78 (226) 6.69 (2.05) Median 6.30 6.30
Min:Max 2.8:20.6 2.8:18.0 Change from baseline to Week 30 Number
364 364 LS Mean (SE).sup.a -0.35 (0.142) -0.46 (0.138) LS mean
difference (SE) 0.11 (0.162) -- vs insulin glargine.sup.a 95% CI
(-0.207 to 0.428) -- p-value 0.4951 -- .sup.aMixed-effect model
with repeated measures (MMRM) with treatment groups (fixed ratio
combination and insulin glargine), randomization strata of HbA1c
(<8.0, .gtoreq.8.0%) at Visit 5 (Week -1), randomization strata
of metformin use at screening (Yes, No), scheduled visit,
treatment-by-visit interaction and country as fixed effects, and
baseline fasting plasma glucose value-by-visit interaction as a
covariate.
[1517] Countries with fewer than 5 patients were grouped with the
country with the lowest number of patients that is 5 or more.
[1518] The analysis included all scheduled measurements obtained
during the study, including those obtained and after IMP
discontinuation or introduction of recue therapy. Included are
patients who have measurements at baseline and post-baseline.
[1519] FIG. 14 shows a plot of mean fasting plasma glucose by
visit
TABLE-US-00056 TABLE 18 Number (%) of patients reaching HbA1c <
7% at Week 30 with no documented (plasma glucose .ltoreq. 70 mg/dL
[3.9 mmol/L]) symptomatic hypoglycemia during the study-mITT
population HbA1c < 7% with Fixed Ratio Insulin no documented
Combination Glargine symptomatic hypoglycemia (N = 366) (N = 365)
Number 366 365 Yes 116 (31.7%) 68 (18.6%) Proportion difference
(95% 13.22% -- CI) vs. insulin glargine.sup.a (7.12% to 19.32%)
.sup.aWeighted average of proportion difference between treatment
groups (fixed ratio combination and insulin glargine) from each
strata (randomization strata of HbA1c < 8.0, .gtoreq.8.0%] at
Visit 5 (Week -1), randomization strata of metformin use at
screening [Yes, No]) using Cochran-Mantel-Haenszel (CMH)
weights.
[1520] Documented symptomatic hypoglycemia is an event during which
typical symptoms of hypoglycemia are accompanied by a measured
plasma glucose of 70 mg/dL (3.9 mmol/L).
[1521] The analysis included all HJbA1c measurements at week 30,
including those obtained after the UMP discontinuation or the
introduction of rescue mediation. Patients were treated as
non-responders if they have no HbA1c assessments at week 30. All
documented symptomatic hypoglycemia occurred during the 30-week
open-label treatment period was considered, including those
occurred after the IMP discontinuation or the introduction of recue
medication.
TABLE-US-00057 TABLE 19 Number (%) of patients requiring rescue
therapy during the 30 week open-label treatment period-mITT
population Fixed Ratio Insulin Combination Glargine Requiring
rescue therapy (N = 366) (N = 365) Number 366 365 Yes 10 (2.7%) 22
(6.0%) Proportion difference (95% -3.35% -- CI) vs. insulin
glargine.sup.a (-6.33% to -0.36%) .sup.aWeighted average of risk
difference between treatment groups (fixed ratio combination and
insulin glargine) from each strata (randomization strata of HbA1c
[<8.0, .gtoreq.8.0%] at Visit 5 (Week -1), randomization strata
of metformin use at screening [Yes, No]) using
Cochran-Mantel-Haenszel (CMH) weights. .sup.bBased on CMH method
stratified by randomization strata of HbA1c [<8.0, .gtoreq.8.0%]
Visit 5 (Week -1) and randomization strata of metformin use at
screening [Yes,No].
3.3 Safety
[1522] Symptomatic hypoglycemia events were documented on a
specific hypoglycemia event form, and not an AE CRF page, and thus
were not included in the TEAE summaries. They are summarized
separately (see Section 3.3.5).
3.3.1 Treatment-Emergent Adverse Events
TABLE-US-00058 [1523] TABLE 20 Overview of adverse event profile:
treatment emergent adverse events-Safety population Fixed Ratio
Insulin Combination Glargine n (%) (N = 365) (N = 365) Patients
with any TEAE 195 (53.4%) 191 (52.3%) Patients with any serious 20
(5.5%) 18 (4.9%) TEAE Patients with any TEAE 1 (0.3%) 2 (0.5%)
leading to death Patients with any TEAE 10 (2.7%) 3 (0.8%) leading
to permanent treatment discontinuation TEAE: Treatment Emergent
Adverse Event n (%) = number and percentage of patients with at
least one TEAE
TABLE-US-00059 TABLE 21 Number (%) of patients experiencing common
TEAE(s) (PT .gtoreq. 3% in any treatment group) by primary SOC and
PT-Safety population Fixed Ratio Insulin Primary System Organ Class
Combination Glargine Preferred Term n(%) (N = 365) (N = 365) Any
TEAE 195 (53.4%) 191 (52.3%) Infections and infestations 98 (26.8%)
112 (30.7%) Influenza 15 (4.1%) 11 (3.0%) Nasopharyngitis 32 (8.8%)
32 (3.8%) Upper respiratory tract infection 13 (3.6%) 11 (3.0%)
Nervous system disorders 39 (10.7%) 19 (5.2%) Headache 21 (5.8%) 10
(2.7%) Gastrointestinal disorders 62 (17.0%) 29 (7.9%) Diarrhoea 16
(4.4%) 30 (2.7%) Nausea 38 (10.4%) 2 (0.5%) Vomiting 13 (3.6%) 2
(0.5%) TEAE: Treatment emergent adverse event, SOC: System Organ
Class, PT: Preferred Term. MedDRA version: 18.0 n (%) = number and
percentage of patients with at least one TEAE. Note: Table sorted
by SOC internationally agreed order and PT alphabetic order. Only
SOC with at least one PT .gtoreq. 3% in at least one group are
presented.
[1524] Note: Table sorted by SOC internationally agreed order and
PT alphabetic order. Only SOC with at least one PT 3% in at least
one group are presented.
3.3.2 Deaths, Serious Treatment-Emergent Adverse Events
[1525] Three patients experienced at least 1 TEAE leading to death:
1 from the combination group, 2 from the insulin glargine group:
[1526] Combination group: [1527] A 74 year-old male patient (ID
840519010) died of pneumonia. The event was not considered as
possibly related to the IMP by the Investigator. [1528] Insulin
glargine group: [1529] A 63 year-old female patient (ID 840550018)
died of gallbladder cancer. [1530] A 54 year-old male patient (ID
703504004) died of cardiopulmonary failure. Patient's medical
history included hypertension. 171 days after the first dose of
IMP, the patient experienced cardiorespiratory failure
(intensity-severe) and died on the same day at 09:32 hours at home.
Autopsy was performed and the cause of death was reported as
cardiorespiratory failure, heart hypertrophy, and coronary
atherosclerosis grade III. No any other AEs or hypoglycemia were
reported during the study.
[1531] These 2 fatal events for 2 patients were not considered as
possibly related to the IMP by the Investigator.
TABLE-US-00060 TABLE 22 Number (%) of patients experiencing serious
TEAE(s) presented by primary SOC, and PT-Safety population Fixed
Ratio Insulin Primary System Organ Class Combination Glargine
Preferred Term [n (%)] (N = 365) (N = 365) Any serious TEAE 20
(5.5%) 18 (4.9%) Infections and infestations 1 (0.3%) 3 (0.8%)
Osteomyelitis 0 1 (0.3%) Pneumonia 1 (0.3%) 1 (0.3%) Wound
infection 0 1 (0.3%) Neoplasms benign, malignant and 4 (1.1%) 2
(0.5%) unspecified (incl cysts and polyps) Benign breast neoplasm 1
(0.3%) 0 Benign gastric neoplasm 1 (0.3%) 0 Breast cancer 1 (0.3%)
0 Gallbladder cancer 0 1 (0.3%) Kaposi's sarcoma 0 1 (0.3%)
Squamous cell carcinoma of the tongue 1 (0.3%) 0 Metabolism and
nutrition disorders 2 (0.5%) 1 (0.3%) Hypoglycaemia 2 (0.5%) 1
(0.3%) Nervous system disorders 3 (0.8%) 0 Hypoglycaemic seizure 1
(0.3%) 0 Hypoglycaemic unconsciousness 2 (0.5%) 0 Eye disorders 0 1
(0.3%) Glaucoma 0 1 (0.3%) Cardiac disorders 7 (1.9%) 2 (0.5%)
Acute myocardial infarction 2 (0.5%) 0 Angina unstable 2 (0.5%) 0
Arteriosclerosis coronary artery 1 (0.3%) 0 Cardiac failure
congestive 0 1 (0.3%) Cardiopulmonary failure 0 1 (0.3%) Myocardial
infarction 1 (0.3%) 0 Supraventricular tachycardia 1 (0.3%) 0
Vascular disorders 0 1 (0.3%) Hypertension 0 1 (0.3%) Hepatobiliary
disorders 1 (0.3%) 1 (0.3%) Cholecystitis acute 0 1 (0.3%)
Cholecystitis chronic 1 (0.3%) 0 Musculoskeletal and connective 2
(0.5%) 1 (0.3%) tissue disorders Intervertebral disc protrusion 0 1
(0.3%) Osteoarthritis 1 (0.3%) 0 Tendonitis 1 (0.3%) 0 Renal and
urinary disorders 0 1 (0.3%) Renal impairment 0 1 (0.3%)
Reproductive system and breast disorders 0 1 (0.3%) Benign
prostatic hyperplasia 0 1 (0.3%) General disorders and
administration 0 3 (0.8%) site conditions Chest discomfort 0 1
(0.3%) Non-cardiac chest pain 0 2 (0.5%) Injury, poisoning and
procedural complications 2 (0.5%) 1 (0.3%) Meniscus injury 0 1
(0.3%) Scar 1 (0.3%) 0 Subdural haematoma 1 (0.3%) 0 TEAE:
Treatment Emergent Adverse Event, SOC: System Organ Class, PT:
Preferred Term. MedDRA version: 18.0 n (%) = number and percentage
of patients with at least one serious TEAE. Note: Table sorted by
SOC internationally agreed order and PT alphabetic order.
3.3.3 Adverse Events Leading to Withdrawal
TABLE-US-00061 [1532] TABLE 23 Number (%) of patients experiencing
TEAE(s) leading to permanent treatment discontinuation by primary
SOC and PT-Safety population Fixed Ratio Insulin Primary System
Organ Class Combination Glargine Preferred Term [n (%)] (N = 365)
(N = 365) Any TEAE leading to permanent 10 (2.7%) 3 (0.8%)
treatment discontinuation Infections and infestations 1 (0.3%) 0
Pneumonia 1 (0.3%) 0 Neoplasms benign, malignant and 1 (0.3%) 1
(0.3%) unspecified (incl cysts and polyps) Benign gastric neoplasm
1 (0.3%) 0 Gallbladder cancer 0 1 (0.3%) Nervous system disorders 2
(0.5%) 0 Dizziness 1 (0.3%) 0 Hypoglycaemic unconsciousness 1
(0.3%) 0 Cardiac disorders 1 (0.3%) 1 (0.3%) Angina unstable 1
(0.3%) 0 Cardiopulmonary failure 0 1 (0.3%) Gastrointestinal
disorders 4 (1.1%) 0 Nausea 4 (1.1%) 0 Pregnancy, puerperium and
perinatal conditions 0 1 (0.3%) Pregnancy 0 1 (0.3%) Investigations
1 (0.3%) 0 Weight increased 1 (0.3%) 0 TEAE: Treatment Emergent
Adverse Event, SOC: System Organ Class, PT: Preferred Term. MedDRA
version: 18.0 n (%) = number and percentage of patients with at
least one TEAE leading to permanent treatment discontinuation.
Note: Table sorted by SOC internationally agreed order and PT
alphabetic order.
3.3.4 Other Significant Adverse Events
Local Tolerability
TABLE-US-00062 [1533] TABLE 24 Number (%) of patients experiencing
injection site reactions during the on-treatment period-Safety
population Fixed Ratio Insulin Event source Combination Glargine
Preferred Term (N = 365) (N = 365) Any injection site reactions 0 2
(0.5%) PT's coded from the investigator 0 2 (0.5%) reported terms
Injection site hypertrophy 0 1 (0.3%) Injection site reaction 0 1
(0.3%) ARAC = Allergic Reaction Assessment Committee, PT =
Preferred term. Note: The on-treatment period is defined as the
time from the first injection of IMP up to 3 days after the last
injection of IMP, regardless of the introduction or rescue
therapy.
Allergic Reactions
TABLE-US-00063 [1534] TABLE 25 Number (%) of patients with events
adjudicated as allergic reaction by ARAC during on-treatment
period-Safety population MedDRA Relationship coded to study ARAC
term (PT) Fixed Ratio Insulin treatment (by diagnosis for ARAC
Combination Glargine ARAC) categories diagnosis (N = 365) (N = 365)
All Any category Any event 0 1 (0.3%) Other 0 1 (0.3%) Rhinitis
allergic 0 1 (0.3%) Not Related to IMP 0 1 (0.3%) Other 0 1 (0.3%)
Rhinitis allergic 0 1 (0.3%) ARAC = Allergic Reaction Assessment
Committee, IMP = Investigational medicinal product. Note: The
on-treatment period is defined as the time from the first injection
of IMP up to 3 days after the last injection of IM, regardless of
the introduction of rescue therapy.
Pancreatic Events
[1535] No events were adjudicated as pancreatitis by the PSAC. In
addition, no pancreatic neoplasms were reported in the study.
Major Cardiovascular Events
TABLE-US-00064 [1536] TABLE 26 Number (%) of patients with events
adjudicated as major cardiovascular events by CAC during the
on-treatment period-Safety population Fixed Ratio Insulin
Combination Glargine n(%) (N = 365) (N = 365) Any 5 (1.4%) 4 (1.1%)
Cardiovascular death 0 1 (0.3%) Non-fatal myocardial infarction 2
(0.5%) 0 Non-fatal stroke 0 0 Hospitalization for unstable angina 0
0 Hospitalization for heart failure 0 1 (0.3%) Coronary
revascularization procedure 5 (1.4%) 3 (0.8%) CAC = Cardiovascular
Events Adjudication Committee n (%) = number and percentage of
patients with events adjudicated as major cardiovascular evens by
CAC. Note: The on-treatment period is defined as the time from the
first injection of IMP up to 3 days after the last injection of
IMP, regardless of the introduction of rescue therapy.
Increased Calcitonin
TABLE-US-00065 [1537] TABLE 27 Number (%) of patients with events
reported on the AE form for increased calcitonin (.gtoreq.20 ng/L)
during the on-treatment period-Safety population Fixed Ratio
Insulin Combination Glargine Preferred Term (N = 365) (N = 365) Any
0 2 (0.5%) Blood calcitonin locreasred 0 2 (0.5%) n (%) = number
and percentage of patients with any cases reported on the AE form
for increased calcitonin .gtoreq. 20 pg/mL along with complementary
form. Note: The on-treatment period is defined as the time from the
first injection of IMP up to 3 days after the last injection of
IMP, regardless of the introduction of rescue therapy.
Increased ALT
TABLE-US-00066 [1538] TABLE 28 Number (%) of patients with events
reported on the AE form for ALT increase during the on-treatment
period-Safety population Fixed Ratio Insulin Combination Glargine
Preferred Term (N = 365) (N = 365) Any 1 (0.3%) 2 (0.9%) Alanine
aminotransferase increased 0 2 (0.5%) Hepatic enzyme increased 1
(0.3%) 0 n (%) = number and percentage of patients with an cases
reported on the AE form for ALT increase along with complementary
form. Note: The on-treatment period is defined as the time from the
first injection of IMP up to 3 days after the last injection of
IMP, regardless of the introduction of rescue therapy.
Pen-Related Events
TABLE-US-00067 [1539] TABLE 29 Number (%) of patients with events
reported in pen-related event questionnaire during the on-treatment
period-Safety population Fixed Ratio Insulin Combination Glargine
(N = 365) (N = 365) Any pen-related events 11 (3.0%) 15 (4.1%)
Associated with a clinical event 0 0 Not associated with a clinical
event 11 (3.0%) 15 (4.1%) Clinical event = symptomatic hypoglycemic
even, hyperglycemic adverse event or other adverse event collected
in pen-related questionnaire. Note: The on-treatment period is
defined as the time from the first injection of IMP up to 3 days
after the last injection of IMP, regardless of the introduction of
rescue therapy.
3.3.5 Other Safety Observation--Symptomatic Hypoglycemia
TABLE-US-00068 [1540] TABLE 30 Summary of symptomatic hypoglycemia
recorded on the dedicated eCRF and meeting protocol definition
during the on-treatment period-Safety population Fixed Ratio
Insulin Combination Glargine (N = 365) (N = 365) Total patient
years of exposure 201.9 208.6 Symptomatic hypoglycemia Number of
patients with events, n (%) 152 (41.6%) 161 (44.1%) Number of
patients with events per patient year .sup.a 0.75 0.77 Number of
events 639 910 Number of events per patient year .sup.b 3.17 4.36
Documented symptomatic hypoglycaemia (plasma glucose .ltoreq. 70
mg/dL [3.9 mmol/L]) Number of patients with events, n (%) 146
(40.0%) 155 (42.5%) Number of patients with events per patient year
.sup.a 0.72 0.74 Number of events 612 880 Number of events per
patient year .sup.b 3.03 4.22 Documented symptomatic hypoglycaemia
(plasma glucose < 60 mg/dL [3.3 mmol/L]) Number of patients with
events, n (%) 89 (24.4%) 83 (22. Number of patients with events per
patient year .sup.a 0.44 0.40 Number of events 229 235 Number of
events per patient year.sup.b 1.13 1.13 Probable symptomatic
hypoglycaemia Number of patients with events, n (%) 13 (3.6%) 20 (5
Number of patients with events per patient year .sup.a 0.06 0.10
Number of events 22 29 Number of events per patient year .sup.b
0.11 0.14 Severe symptomatic hypoglycaemia Number of patients with
events, n (%) 4 (1.1%) 1 (0. Number of patients with events per
patient year .sup.a 0.02 <0.01 Number of events 5 1 Number of
events per patient year .sup.b 0.02 <0.01 IMP: Investigational
Medicinal Product, eCRF: electronic Case Report Form. Patient years
of exposure: calculated as time from the first to the alst
injection of IMP plus 1 day. .sup.a: Calculated as number of
patients with events divided by total patient years of exposure. b:
Calculated as number of events divided by total patient years of
exposure. Symptomatic hypoglycemia = symptomatic hypoglycemia
recorded on the dedicated eCRF and meeting protocol definition for
severe, or documented, or probable symptomatic hypoglycemia.
[1541] On-treatment period is defined as the time from the first
injection of IMP up to 1 day for symptomatic hypoglycemia after the
last injection of IMP, regardless of the introduction of rescue
therapy.
Sequence CWU 1
1
2144PRTArtificialdesPro36-Exendin-4(1-39)-Lys6-NH2 1His Gly Glu Gly
Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu1 5 10 15Glu Ala Val
Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30Ser Gly
Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys 35 40239PRTHeloderma
suspectum 2His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met
Glu Glu1 5 10 15Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly
Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser 35
* * * * *